Variable symptomatic and neurophysiologic response to HD-tDCS in a case series with posttraumatic stress disorder

Journal Pre-proof Variable symptomatic and neurophysiologic response to HDtDCS in a case series with posttraumatic stress disorder

Benjamin M. Hampstead, Nathan Mascaro, Stephen Schlaefflin, Arijit Bhaumik, Julia Laing, Scott Peltier, Brian Martis PII:

S0167-8760(19)30545-8

DOI:

https://doi.org/10.1016/j.ijpsycho.2019.10.017

Reference:

INTPSY 11674

To appear in:

International Journal of Psychophysiology

Received date:

3 September 2018

Revised date:

22 October 2019

Accepted date:

29 October 2019

Please cite this article as: B.M. Hampstead, N. Mascaro, S. Schlaefflin, et al., Variable symptomatic and neurophysiologic response to HD-tDCS in a case series with posttraumatic stress disorder, International Journal of Psychophysiology(2019), https://doi.org/10.1016/j.ijpsycho.2019.10.017

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2019 Published by Elsevier.

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Variable Symptomatic and Neurophysiologic Response to HD-tDCS in a Case Series with Post Traumatic Stress Disorder

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Benjamin M. Hampstead1-2*, Nathan Mascaro3,4, Stephen Schlaefflin2, Arijit Bhaumik5, Julia

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Laing2, Scott Peltier6-7, Brian Martis1

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Mental Health Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA Neuropsychology Section, Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA 3 Trauma Recovery Program, Atlanta VAMC, Decatur, GA, USA 4 Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA 5 Department of Neurology, University of Michigan, Ann Arbor, MI, USA 6 Functional MRI Laboratory, University of Michigan, Ann Arbor, MI, USA 7 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA

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*Corresponding Author Benjamin M. Hampstead, PhD, ABPP/CN 2101 Commonwealth Blvd, Suite C Ann Arbor, MI 48105 734-763-9259 [email protected]

Keywords: fMRI, tDCS, connectivity, graph theory, anxiety, mood, neuromodulation

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Abstract

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Chronic Posttraumatic stress disorder (PTSD), characterized by symptoms of re-experiencing, hyperarousal, and avoidance, is challenging to treat as a significant proportion of patients remain symptomatic following even empirically supported interventions. The current case series investigated the effects of up to 10 sessions of high definition transcranial direct current stimulation (HD-tDCS) on symptoms of PTSD. Participants received HD-tDCS that targeted the right lateral temporal cortex (LTC; center cathode placed over T8), given this region’s potential involvement in symptoms of re-experiencing and, possibly, hyperarousal. Five of the six enrolled patients completed at least 8 sessions. Of these five, four showed improvement in symptoms of re-experiencing after HD-tDCS. This improvement was accompanied by connectivity change in the right LTC as well as a larger extended fear network but not a control network that consisted of visual cortex regions; however, the nature of the change varied across participants as some showed increased connectivity whereas others showed decreased connectivity. These preliminary data suggest that HD-tDCS may be beneficial for treatment of specific PTSD symptoms, in at least some individuals, and warrants further investigation.

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Introduction Posttraumatic stress disorder (PTSD) is characterized by an intrusive re-experiencing of the traumatic event, hyperarousal, negative alterations in cognition and mood, and avoidance (American Psychological Association, 2013). Although there are several empirically supported treatments, including medications and various forms of psychotherapy (Bisson et al., 2007; Goodson, Helstrom, Halpern, Ferenschak, & Gillihan, 2011; Watts et al., 2013), approximately 33% to 50% of patients continue to meet PTSD diagnostic criteria following such treatments (Bradley, Greene, Russ, Dutra, & Westen, 2005; Van Etten & Taylor, 1998) and continue to experience significant disability that comes at a cost to the individual, community, and nation. As a result, identifying effective alternative or adjunctive interventions has become a priority. There is growing interest in noninvasive brain stimulation techniques as a potential treatment of PTSD given their ability to modulate functioning in particular brain regions and/or networks. The current case series focuses on one such method - transcranial direct current stimulation (tDCS). tDCS modulates neuronal excitability using low intensity electric currents that are typically 1 – 2 milliamps (mA). While the traditional pad-based approach uses a single large anode and cathode (typically 25-35cm2), High Definition (HD-) tDCS provides more focal stimulation delivery (Datta et al., 2009) by surrounding a center electrode with four “ring” electrodes (all about the size of a dime). While this approach enhances focality, it may limit the depth of electrical current penetrance into the brain. However, HD-tDCS has the benefit of providing the full current intensity under the center electrode while at the same time limiting the spread of current to the perimeter of the ring electrodes and also reducing the physiological effects of the current of non-interest by dividing it across the 4 ring electrodes. The standard mechanistic understandings of tDCS holds that neuronal populations under the anode become depolarized (“excited”) while those underlying the cathode become hyperpolarized (“inhibited”) (Nitsche et al., 2008). Although we acknowledge that this mechanistic account is likely overly simplistic and that emerging evidence suggests the effects may depend on a number of factors at both the cellular and systems levels, we maintain this general framework for purposes of the current study. The available evidence suggests that tDCS is both well-tolerated (Brunoni et al., 2011; Reckow et al., 2018) and safe (Bikson et al., 2016) across a wide range of populations. Our previous review of the published literature investigating tDCS (all used traditional pad-based tDCS) as a treatment for those with PTSD and other anxiety revealed, at that time, a total of 9 patients with anxiety disorders (4 with PTSD) who received five to fifteen sessions of tDCS at either 1 or 2 milliamps (mA) disorders (Hampstead, Briceno, Mascaro, Mourdoukoutas, & Bikson, 2016). While the effects varied across studies, there seemed to be a trend in which beneficial effects were found when the cathode was placed over the right hemisphere (e.g., (Narayanaswamy et al., 2015; Shiozawa, da Silva, & Cordeiro, 2014; Shiozawa et al., 2014)). Such findings raise the possibility that the hyperpolarizing (“inhibiting”) effects mitigate the maladaptive hemispheric upregulation associated with anxiety that was posited in prior models (Heller & Nitschke, 1988). Since our review, a double-blind sham-controlled trial of 40 patients with PTSD found initial symptomatic improvement following 10 sessions in which the anode and cathode were placed over the left and right prefrontal cortex (Ahmadizadeh, Rezaei, Fitzgerald, 2019). An additional pilot study suggested tDCS enhances the effects of virtual reality based exposure therapy in those with PTSD (van’t Wout-Frank et al., 2019). Only a single study, to our knowledge, has reported neurophysiologic change (qEEG in P3a) after tDCS in those with PTSD; however, the study design makes it difficult to know whether such changes

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arose from tDCS or the addition of cognitive training. (Saunders et al., 2015). Thus, there is some indication that tDCS may be effective in those with PTSD but little data demonstrating neurophysiological change. The current case series is the first to report symptomatic and neurophysiologic effects (measured via functional magnetic resonance imaging – fMRI) of HD-tDCS in those with PTSD. Our approach was based on both theoretical and neuroanatomical models of PTSD, which we previously described in detail (Hampstead et al., 2016) and briefly review here. Specifically, we used HD-tDCS to target the lateral temporal cortex (LTC) as a “gateway” for disrupting the wellknown “fear circuit” (i.e., amygdala, hippocampus, ventromedial prefrontal cortex (PFC)) believed to underlie PTSD (Etkin & Wager, 2007; Simmons & Matthews, 2012; Skelton, Ressler, Norrholm, Jovanovic, & Bradley-Davino, 2012). The primary problem is that the “deep” nature of these key components prevents selective non-invasive stimulation since the electrical current would need to flow through multiple brain regions before reaching these structures. We determined the LTC was a viable target for stimulation after reviewing multiple complementary lines of research. First, histopathological studies have demonstrated direct reciprocal connections between the LTC, amygdala, and insula in macaque monkeys (Aggleton, Burton, & Passingham, 1980; Amaral & Price, 1984; Mesulam & Mufson, 1982a, 1982b; Mufson & Mesulam, 1982) that are consonant with functional connectivity analyses showing these areas are part of the same functional network (Cauda et al., 2011; Cerliani et al., 2012), generally recognized as the “default mode network” (Greicius, Srivastava, Reiss, & Menon, 2004). Second, classic findings demonstrated that direct electrical stimulation of the LTC elicited vivid, multisensory, autobiographical “flashbacks” (Penfield & Perot, 1963). Third, more recent findings revealed that LTC structural integrity was inversely related to the frequency of traumatic flashbacks in patients with PTSD (Kroes, Whalley, Rugg, & Brewin, 2011) and that the strength of connectivity between the insula and lateral cortex was positively related to symptoms of reexperiencing (Sripada et al., 2012). Fourth, findings that the LTC and insula are hyperactivated (both regions via fMRI (Etkin & Wager, 2007); LTC via magnetoencephalography (Engdahl et al., 2010)) in patients with PTSD and other anxiety disorders and, importantly, that this is attenuated in those who no longer met criteria for PTSD (Engdahl et al., 2010). Together, these findings suggest the LTC and insula may interact with the fear circuit to form a feedback loop that propagates the maladaptive symptoms of PTSD. Thus, our primary hypothesis was that disrupting this loop via the presumed hyperpolarizing effects of cathodal stimulation over the LTC would result in symptomatic improvement and be reflected by altered connectivity strength between this extended fear network (EFN - i.e., LTC, insula, amygdala, hippocampus, dorsomedial PFC) as measured by resting-state fMRI. Methods Participants and general study methods The study was approved by the Institutional Review Boards of the VA Ann Arbor Healthcare System and the University of Michigan. All participants provided written informed consent in accordance with the Declaration of Helsinki. The study was registered with clinicaltrials.gov (NCT02442843) and initially focused on male combat Veterans with the goal of randomizing 30 participants to active or sham HD-tDCS using the parameters described below. However, recruitment challenges caused us to expand our inclusion criteria to include females and all cause PTSD (March, 2017). The final sample included 4 male Veterans with

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combat related PTSD and two females with PTSD arising from sexual trauma and exposure to traumatic deaths (see Table 1). Throughout the study, inclusion criteria required a diagnosis of PTSD based on DSM-IV criteria. Common comorbid Axis I diagnoses, such as other Anxiety disorders or Major Depressive Disorder, were allowed. Most participants met criteria for either Major Depressive Disorder (MDD) or Generalized Anxiety Disorder (GAD) based on the MINI, though symptom severity often did not suggest acute distress (see HDRS and STAI in Table 1). All participants were required to be stable on medications for at least 2 weeks prior to study enrollment and to pass symptom validity measures. General exclusion criteria included active substance abuse/dependence, other Axis I (e.g., schizophrenia, bipolar disorder) or any Axis II disorders, MRI contraindications, tDCS contraindications (e.g., metallic/electronic implants, skin conditions that could interact with stimulation (e.g., eczema, psoriasis, open wounds, seizure disorder or history of neurologic disease, substance abuse/dependence), or failing symptom validity testing. Only one participant (PT3) ostensibly met possible criteria for alcohol use disorder via the Mini International Neuropsychiatric Interview (MINI); however, further evaluation revealed an average consumption of 1-2 beers and no functional impairment. This level of consumption was maintained throughout the study period without incident. Participants underwent a baseline evaluation that included the Mini International Neuropsychiatric Interview (MINI), Clinician-Administered PTSD Scale for DSM-IV (CAPS), PTSD Checklist – Civilian Version (PCL-C), State Trait Anxiety Inventory (STAI), Combat Exposure Scale (CES), Morel Emotional Numbing Test (MENT), Hamilton Depression Rating Scale (HDRS), subtests of the NIH Toolbox (Picture Vocabulary Test (administered only at baseline), Flanker, Dimensional Change Card Sort, and Pattern Comparison), and the Hopkins Verbal Learning Test (HVLT). A licensed PhD level Psychologist, who was blinded to stimulation condition, administered the MINI (baseline only), CAPS, PCL-C, and HDRS both before and after the intervention. Study staff administered the remainder of the measures. All participants were additionally required to meet PTSD criteria based on the CAPS at the time of enrollment. Eligible participants then underwent a baseline fMRI scan, up to 10 HD-tDCS sessions on consecutive weekdays (Monday through Friday for two consecutive weeks as their schedule permitted), and then a repeat evaluation and fMRI scan 3 – 4 days after the final HDtDCS session (see Figure 1). The delay between the last HD-tDCS session and repeat evaluation/fMRI scanning was designed to evaluate more clinically oriented and persistent effects of stimulation as opposed to the standard 30-60 minute after effect period used in many cognitive neuroscience studies. Of 22 potential patients who passed an initial record review, we excluded 16 individuals after the intake evaluation because they did not meet inclusion criteria (n=11), 4 declined to participate due to the required time commitment, and the final patient was unable to participate due to a family emergency. A total of 6 patients (4 male) met all inclusion criteria. The first participant was enrolled as methodological changes were being approved by the IRBs. Thus, he received 5 sessions of sham HD-tDCS followed by 5 sessions of active HD-tDCS (note the patient was unaware of the stimulation condition). The remaining five patients were randomized to active or sham HD-tDCS during the first stimulation session and underwent fMRI scanning (see below) approximately 20 minutes after stimulation ended (data not reported here). These participants then received up to 9 additional active HD-tDCS sessions (depending on their availability) but were not explicitly told they would be receiving active stimulation. One

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participant was subsequently excluded (see Tolerability and Adverse Events below). Thus, our primary sample consists of 5 patients. A group of 12 demographically comparable participants with a history of combat experience (n=11 male) and one female with no history of Axis I or II disorders served as our reference control group. The same exclusionary criteria applied to this group. One male participant was ultimately excluded due to failed symptom validity testing. These participants underwent the same baseline study procedures and fMRI sequences as did the patients and, hence, provide normative data for the graph theory metrics. Although the sample size of this control group was limited, we used their fMRI data to establish normative values (i.e., z-scores as described below) since 1) the group is comparable in background with the participants diagnosed with PTSD, 2) their data were collected on the same fMRI equipment using the same parameters. Participant characteristics are shown in Table 1.

fMRI parameters: Structural imaging data were collected using a GE MR750 3T MRI scanner (GE, Milwaukee, WI) with a 32-channel phased array head coil (Nova Medical, Wilmington, MA). Sequence parameters for structural acquisition were: Field of view (FOV) = 256, Matrix = 6

Journal Pre-proof 256 × 256, 156 slices per volume, 1 mm3 voxel size, TR = 12 ms, TE = 5 ms, TI = 500 ms, flip angle = 15°. For resting state fMRI, participants were instructed to focus their gaze on the fixation cross on the screen and to not fall asleep. Resting state data was acquired through an echo planar imaging (EPI) sequence and parameters were: FOV = 220, Matrix = 64 × 64, 40 slices per volume, 3.4 × 3.4 × 3 mm voxel size, TR = 2000 ms, TE = 26 ms, flip angle = 90°. A total of 300 volumes were used for analysis after discarding 10 initial transitory volumes.

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fMRI analyses: MRI images were preprocessed and analyzed through SPM8 (SPM8; Wellcome Trust Centre for Neuroimaging). Slice timing correction was performed for functional volumes. Functional volumes were realigned to the first volume in the experiment to correct for head motion and co-registered with the high-resolution sagittal images. The structural images were spatially normalized to a standard MNI template using the voxel-based morphometry toolbox (VBM8 http://dbm.neuro.uni-jena.de/vbm) and DARTEL high-dimensional warping and resampled to a 3x3x3 mm voxel size. Estimated deformation fields from warping were applied to normalize images to MNI space and smoothed using a 5-mm FWHM Gaussian kernel. Motion scrubbing (removal of volumes) was performed based on a framewise displacement threshold of 0.3. An average of 5.08 volumes were scrubbed across all scans for participants with PTSD participants, with a maximum of 35 volumes that surpassed motion threshold. Control participants had less movement with an average of 0.05 scrubbed volumes. All other subjects' (PTSD & Controls) movements were below 1mm. Their translational and rotational motion data as with their first derivative and quadratic terms were added as motion regressors to be regressed out from all voxels. The time course data for each voxel was band-pass filtered (0.01 to 0.10 Hz band) to capture the low-frequency spontaneous BOLD oscillations in resting state signals. White matter and CSF signals were regressed out with the PCA CompCor method as described in Behzadi et al. (2007); however, global signal regression was not used.

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Resting state functional connectivity was examined using pre-defined regions of interest (ROI) based on our primary hypothesis. Specifically, we selected 10mm sphere ROIs placed under the center electrode at the right LTC region (represented by a vitamin E capsule during MRI) as well as its counterpart in the left LTC region. For our other regions of interest, including the anterior insula, amygdala, hippocampus, and medial prefrontal cortex within both the right and left hemispheres (i.e., the EFN), anatomical ROIs were defined through the Harvard-Oxford cortical and subcortical structural probabilistic atlases (Desikan et al., 2006) with a 50% threshold for their binary masks. We also created a control network that consisted of 10 ROIs within the visual system (5 in each hemisphere) where the ROIs were selected from the visual network of the Power 264 functional network parcellation (Power et al., 2011) and 5mm spheres were constructed to extract signal correlation (see coordinates in Supplemental Materials Table 1 & 2). Pearson product–moment correlation coefficients were calculated between the average BOLD time course in the predefined ROI regions. Correlation coefficients were then transformed to z scores using a Fisher r to z transformation. Graph theory metrics, specifically nodal strength were calculated through the 'igraph' package in R (Team, 2013). Nodal strength is defined as the summation of edge weights connected to the node of interest. The mean and standard deviation for strength metrics were calculated for the control group and used as normative data for the PTSD patients, whose strength values are represented as the resulting z-scores.

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HD-tDCS parameters: HD-tDCS was administered at 2mA for 20 minutes. The center electrode (cathode) was placed at T8 while the ring anodes were placed at F8, C4, P8, and EX10. As shown in Figure 2, this montage effectively targeted the right LTC with little to no current affecting other brain regions or subcortical structures. Stimulation was performed in a quiet office setting. Trained research staff first examined the scalp for any evidence of skin damage/compromise (none were evident during the study). They then measured and marked participants’ heads and placed electrodes at the appropriate locations using head netting (Surgilast, a tubular elastic dressing retainer manufactured by Derma Sciences) to hold them in place. Participants were instructed to sit quietly and relax during the stimulation session. A study team member remained in the room for monitoring purposes and was instructed to remain silent unless the participant had specific questions. Participants completed a standardized side-effects questionnaire (Brunoni et al., 2011) after the 20 minutes of stimulation ended, after which electrodes were removed and the sites inspected for redness or any other evidence of skin damage.

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Statistical analyses: Given the case series nature of the study, we focus primarily on a descriptive approach and effect sizes rather than on inferential statistics. This approach is appropriate given 1) the case-series format, 2) the greater potential harm at this stage in concluding HD-tDCS had no effect (i.e., mitigating a potentially beneficial treatment), and 3) with recent position statements from leading statisticians emphasizing effect sizes over p-values (see Wasserstein, Schirm, Lazar, 2019). Interpretation of effect sizes followed Cohen’s convention. As noted above, connectivity strength for the right LTC, EFN, and visual network were calculated for each participant with PTSD and then transformed into z-scores using the mean and standard deviation of the control group for each area/network. Change from baseline was calculated by subtracting baseline from post-treatment values. Results Pre-tDCS Findings: Before evaluating the effects of HD-tDCS, we felt it important to examine the relationship between PTSD severity, as measured by the CAPS, and the targeted right LTC, the EFN, and the visual (control) network using our limited dataset. Participants with PTSD showed relatively increased connectivity within both the right LTC (average z-score = +0.65 (SD=.685)) and the EFN (average z-score = +0.78 (SD=.531)) but nominally weaker connectivity in the visual network (average z-score = -0.32 (SD=.296)) relative to the control group. This pattern tends to support prior findings of EFN hyperactivity in those with PTSD as well as our specific hypothesis that the right LTC has biological significance in PTSD. We also examined the relationships between CAPS scores and mean connectivity strength. Figure 3

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shows that connectivity strength of the right LTC was strongly and uniquely related to scores on the Re-experiencing scale of the CAPS (Cluster B; R2 = 0.853) in an inverse manner (i.e., greater LTC connectivity was associated with fewer symptoms of re-experiencing). Importantly, these relationships were not evident in either of the network-level analyses, although we recognize that some medium effect sizes were present. In contrast, the strength of EFN connectivity showed the strongest relationship with the Hyperarousal scale (CAPS Cluster D; R2 = 0.242). Thus, the right LTC appears to be a viable target for symptoms of re-experiencing as we initially posited, though we emphasize that future studies with larger sample sizes are needed to verify this possibility.

Tolerability and Adverse Events: Tolerability data were acquired upon completion of each session using a standardized form (Brunoni et al., 2011). All data were within the expected ranges as shown in Supplementary Tables 3 and 4. One participant (PT4) was administratively withdrawn after 4 sessions due to persistent and atypical complaints about tinnitus that were present at the time of enrollment. This patient reported intermittent worsening of these symptoms that occurred hours after the initial fMRI and prior to his second HD-tDCS session (i.e., about 24 hours after completion of stimulation). These complaints were not present during or within the 30-45 minutes he remained in our office after completion of any session. Rather, he reported a subjective worsening of tinnitus several hours later that appeared to have a temporal relationship with emotionally charged situations that occurred in his personal life on those particular days. This series of events was reported to the IRB and it was ultimately considered unrelated to the

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Journal Pre-proof study methods. Overall then, stimulation was well tolerated and there were no unexpected or severe adverse events attributable to HD-tDCS.

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Effects of HD-tDCS: There was variability in response to HD-tDCS that appears unrelated to the severity of PTSD symptoms at the time of enrollment (whether via CAPS or PCL-C)(Table 1). Figure 4A demonstrates this variability by showing post-treatment scores as a percentage of change from baseline and reveals that the most consistent changes were evident in 4 of the 5 participants on the CAPS Total score (7-57% improvement) and Cluster B (9–84% improvement). Four patients also reported 19-38% improvement on the PCL-C (Table 1). Changes in connectivity strength are shown in Figure 4B. The targeted right LTC showed the greatest overall change following HD-tDCS, followed by the EFN, and the least amount of change in the untargeted visual (control) network. Thus, stimulation effects appeared restricted to the targeted area and associated network. Within this context, however, the direction of change differed by participant. Regarding individual participants, three (PT2, PT3, PT5) reported consistent improvement on overall measures of PTSD severity (CAPS Total; PCL-C) as well on Cluster B. PT2 and PT3 both showed increased connectivity in the LTC and EFN that accompanied the above noted symptomatic improvement while PT5 showed decreased LTC but increased EFN connectivity. PT6 consistently reported improvement in overall symptoms (CAPS Total = 9%; PCL-C = 19%) that was also accompanied by reduced LTC and EFN connectivity. However, she reported a relative worsening on CAPS Clusters B (re-experiencing; 21%) and D (hyperarousal; 31%) that occurred within the context of marked reduction in Cluster C (avoidance; 54%). In each of these 4 cases, the magnitude of change in the LTC and EFN was notably different than in the visual network. Only PT1, who received the fewest number of active HD-tDCS sessions (n=5), reported very slight increases on the CAPS Total (3% increase) and PCL-C (6% increase) as well as slight reduction on Cluster B (42% but raw change of -3). This participant showed relatively comparable connectivity reductions of 7-12% across the LTC, EFN, and visual network that accompanied the nominal symptomatic changes.

For exploratory purposes, we examined the relationship between change in symptoms, as measured by CAPS scores, and change in connectivity strength (Figure 5). Change in the CAPS

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Total and Cluster B (Re-experiencing) scores was specifically related to the right LTC and the EFN but not to the visual network. Removing the patient with the greatest CAPS change (PT3) still yielded large effect sizes for the right LTC and CAPS Total change (R2=.317) and Cluster B (R2=.701) as well as for the EFN and Cluster B (R2=.584); however, EFN and CAPS Total change (R2=.01) were unrelated in that instance.

Discussion Despite the small, case-series nature of this study, the findings are the first, to our knowledge, to directly examine the efficacy of HD-tDCS on PTSD symptoms and the associated neurophysiologic underpinnings. Based on the results of several independent lines of investigation, we first hypothesized that the right LTC was part of an extended fear network (EFN) and that connectivity between this region and the larger EFN would be related to symptoms of PTSD – specifically those related to re-experiencing and hyperarousal. We used a control network of visual cortex regions that did not experience direct stimulation to demonstrate the specificity of our findings (see Figure 2). We also hypothesized that targeting the right LTC using HD-tDCS would alter connectivity and result in symptomatic improvement. Although the ultimate sample size was far below our goal, the results provide promising preliminary evidence supporting the study hypotheses.

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The findings support our first hypothesis by showing that connectivity of the right LTC and the EFN were, respectively, two-thirds and three-quarters a standard deviation greater in the PTSD than the control group. These findings are consonant with earlier work showing hyperactivity/connectivity of these areas (Engdahl et al., 2010; Etkin & Wager, 2007). Moreover, these regions appear to be functionally important since connectivity strength of the right LTC was strongly related to symptoms of re-experiencing and the EFN was related to hyperarousal. The inverse nature of these relationships is consistent with earlier work suggesting greater symptom severity as structural integrity of the LTC decreased (Kroes et al., 2011) but is ostensibly at odds with what could be concluded based on prior fMRI/MEG evidence (i.e., more activity/connectivity equals more symptoms). The implications of this finding warrant further investigation since they could represent 1) critical methodologic differences (e.g., prior taskbased fMRI versus our use of graph theory in resting-state fMRI; group summary statistics vs. a correlation approach) or 2) theoretical ramifications – such as greater network connectivity actually functions in a protective manner. This latter possibility suggests the goal should be to enhance, rather than disrupt, connectivity in order to reduce symptom severity – a possibility we return to below. Importantly, such relationships were nominally evident in the visual network, thereby adding to the functional specificity of the LTC as it relates to symptoms of PTSD. Our second hypothesis that HD-tDCS would disrupt right LTC and EFN connectivity and result in symptomatic improvement met with variability across the five patients. Encouragingly, four of the five patients demonstrated reduced overall severity as well as symptoms of reexperiencing (CAPS B) with post-treatment levels 9-84% below baseline. This symptomatic change was mirrored by altered connectivity of both the right LTC and the EFN (Figure 5) that was specific to these areas and symptoms in 4 of the 5 participants (all but PT1, who demonstrated a general decline in connectivity across the regions evaluated). However, the nature of connectivity change varied across participants. The only other study of those with PTSD also reported variability in their four patients who underwent once weekly tDCS combined with cognitive training (Saunders et al., 2015). Variability in response is increasingly recognized in the larger field of tDCS (Wiethoff, Hamada, & Rothwell, 2014) and represents an important area for future study. In this respect, our use of a center cathode may have contributed to the variable response since the cathode is known to have more inconstant effects (Jacobson, Koslowsky, & Lavidor, 2012), including both “inhibitory” and “excitatory” effects (Batsikadze, Moliadze, Paulus, Kuo, & Nitsche, 2013). Thus, we cannot rule out the possibility that our results reflect such findings and advocate for future studies evaluate the amount of electrical current being delivered to the targeted brain area via individualized MRI based computational electrical models. Unfortunately, we were not able to develop such models for the current study. Regardless, our findings provide preliminary evidence of symptomatic improvement and corresponding change in specific brain regions and associated networks in at least a subset of patients with PTSD. It is also important to document the tolerability and safety of HD-tDCS as well as any effects on other comorbid symptoms in this population. Tolerability, as measured using a standardized questionnaire, was high, with mild symptoms of itching and tingling being most commonly reported (see Supplemental Table 3). Such results are consonant with data from traditional pad-based tDCS (Brunoni et al., 2011) and our recent HD-tDCS report (Reckow et al., 2018). Although PT4 was ultimately withdrawn from the study, his tolerability data were no different than the remainder of the patients (see Supplemental Table 3 & 4). There were no unexpected events related to safety in the study. As noted above, PT4’s report of increased

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tinnitus occurred hours after each session ended and in conjunction with emotionally charged events. Just as we cannot be certain HD-tDCS was unrelated to this perceived symptomatic worsening, we also cannot rule out the possibility that HD-tDCS temporarily reduced symptoms of tinnitus (e.g., (Fregni et al., 2006)) and that the patient’s impression of worsening was actually symptomatic return when HD-tDCS effects wore off hours later. Future studies should be vigilant to such possibilities. There was no clear evidence of cognitive change on any of the NIH Toolbox measures or on verbal learning or memory (i.e., HVLT-R). Likewise, there was no clear pattern of change in other comorbid conditions, like general anxiety (e.g., STAI) or depression (e.g., HDRS). Two patients (PT1, PT6) showed relative increases in post-treatment HDRS scores but it is difficult to determine whether this represents a data trend, an expected pattern of variability in those with chronic PTSD, or patient-specific factors (e.g., PT6 reported fewer symptoms of avoidance at post-treatment, which raises the possibility that she was focusing more on the traumatic event and experiencing a reduced mood as a result). Thus, we cannot rule out the possibility that such comorbid conditions affected the findings and advocate for the consideration of such factors in future work. The small sample size is the greatest limitation of the study and we encourage replication and extension of our findings. We attempted to address this limitation by creating a specific network (i.e., EFN) and a comparably sized control network that consisted of visual regions that were unaffected by HD-tDCS according to the finite element model (Figure 2). The resulting specificity of the symptomatic and neurophysiologic change is both theoretically and functionally plausible; however, we lacked the statistical power to examine whole brain connectivity and cannot address whether other regions or networks would have shown comparable (or even greater) effects. Other aspects of dosing should also be investigated as PT1 received the fewest number of sessions (n=5) and experienced the weakest symptomatic and non-specific neurophysiologic response (though other patient-specific factors may account for such findings). Examining the combination of HD-tDCS and established psychotherapeutic approaches (e.g., prolonged exposure therapy) may hold particular promise and was originally planned as a follow-up study. We are currently evaluating such a synergistic approach in other populations (Hampstead, Sathian, Bikson, & Stringer, 2017) and note a recently published pilot study that suggests tDCS enhanced virtual reality based exposure therapy (van’t Wout-Frank et al., 2019). Similarly, interactions with medications should be evaluated given an initial review revealing both enhancing and impeding interactions with tDCS (McLaren, Nissim, Woods, 2017). Finally, we acquired post-treatment outcome data 3 – 4 days after the last HD-tDCS session in order to emulate a more clinically-oriented approach; however, future work will be needed to determine whether this was optimal for measuring HD-tDCS effects. While far from definitive, our preliminary findings provide intriguing support that 8 – 10 sessions of HD-tDCS at 2mA over the right LTC appears to hold potential for at least a subset of those with PTSD. Future studies will need to validate our findings and, if replicated, establish parameters for successful treatment.

Conflict of Interest The authors declare no conflicts of interest. Author Contributions

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Journal Pre-proof All authors read and revised the manuscript prior to submission. Specific author contributions are as follows: BH oversaw all aspects of the study and led interpretation, presentation, and dissemination efforts. SP oversaw for fMRI data analysis and relevant portions of the manuscript. NM assisted with study design and data interpretation. SS, AB, JL were responsible for participant recruitment as well as data collection and organization. BM contributed to medical safety monitoring and to recruitment/characterization efforts. Funding This work was supported by the National Institute of Mental Health (1R21MH102539 to BMH).

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Acknowledgements The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. We wish to acknowledge Drs. Sarah Garcia and Katherine Porter for their assistance with portions of data collection as well as Dr. Frank Hillary for consultation on fMRI methods and Dr. Sean Ma for assistance with fMRI analysis.

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Table 1. Demographic and evaluation data

Age Educat ion Sex CES Number of HD-tDCS sessions (# active) Receiving psychotherapy? Past Week CAPS Severity Cluster B Cluster C Cluster D PCL-C (Modified Total) HDRS STAI

State Trait

MENT NIH Toolbox TPVT

Controls M SD 42.3 17.9 6 12 15.6 2.36 8 9 10 Male, 1 Female 13.7 9.32 N/A N/A 2 0.82 0 1.27 17.1 8 0.83 24.2 7 25.3 6 1.42 113. 44

PT1

PT2

PT3

65

31

53

12

13

16

Male 27

Male 22

10 (5)

10 (10)

3.04 1.83 0 2.76

No Pre 29 7 11 11

Post 30 4 13 13

1.6 1.75

48 5

51 12

4.86

31

5.14 1.88 16

22

20

ro

18

16

13

Male 25

Male 27

Female 0

Female 0

4 (4)

No Pre 54 14 24 16

Post 49 17 11 21

Post 19 3 2 14

Post N/A N/A N/A N/A

38 6

25 5

65 18

N/A N/A

39 7

24 6

46 12

37 17

38

30

38

62

N/A

29

27

40

42

70

46

36

36

64

N/A

41

46

2 81.0 1

N/A

1

N/A

N/A N/A

1

N/A

101.25

N/A

0 111. 63

44 42 N/A 1 N/A 10 3

l a 56 17

37 11

36

41

34

50

2 93. 43

N/A N/A

59

9 (8) Yes Pre Post 56 52 11 10 27 29 18 13

Post 41 12 14 15

Jo

PT6

No Pre 55 13 21 21

No Pre 45 19 12 14

n r u

PT5

f o

-p

e r P

PT4

No Pre 50 16 12 22

10 (9)

124

8 (8)

N/A N/A 18

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NIH Toolbox Flanker NIH Toolbox DCCS NIH Toolbox Pattern Comparison HVLT Total Learning Delayed Recall Percent Retained Recognition Hits Discrimination

91.8 3 100. 43 96.7 2 53.3 3 9.42 96.3 7 11.4 2 11

9.75 10.8 3 11.1 2

95. 95 94. 37 92. 62

100.6 9 96.54 103.8 7

99.61

87.09 110.7 9

90.68

94.7 3 98.6 5 89.5 3

88.25

89.98

4.72

21

22

24

20

18

24

1.88 11.5 3

6 66. 67

5

9

10

7

9

62.50

113

100

100

0.79

11

10

12

10

0.85

11

9

11

r P

97.55 104.1 8

l a

10

82.15

11

90

f o

11

9

11

9

o r p

e 12

91.2 6 82.8 2 84.5 2 11 4

80

N/A

81

103

N/A

108

125

N/A

130

136

12 4 11 2 12 4

35

36

27

33

12

12

12

100

100

11 11 0

12

12

11

12

12

12

11

12

N/A N/A N/A N/A N/A

91 101 124

109

n r u

Jo

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Highlights  First use of HD-tDCS over the lateral temporal cortex in those with post-traumatic stress disorder  Four of five participants showed some degree of symptomatic relief and neurophysiologic change, as measured via fMRI  Future work could build on these preliminary findings and evaluate individual factors and treatment parameters associated with positive response

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