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In recent years, neuropsychiatric research is pointing to transdiagnostic, neurobiological aberrations specifically involving the so-called core intrinsic connectivity networks c-ICNs which include the default mode network DMN , central executive network CEN and salience network SN [ 30 — 33 ].

Briefly, the DMN is anchored in the posterior cingulate cortex PCC and medial prefrontal cortex mPFC , and putatively subserves internally directed thought [ 34 , 35 ]. Lastly, the SN, anchored in the anterior insula aINS and dorsal anterior cingulate cortex dACC , is believed to be important for the detection of salient stimuli and switching between the other c-ICNs [ 43 , 44 ].

Additionally, the c-ICNs have also been associated with autonomic nervous system ANS modulation [ 45 — 50 ] possibly helping to explain the ANS dysfunction consistently reported across psychopathologies [ 51 , 52 ]. The central tenet of this theory is that the sensorial, cognitive, affective, and behavioural dysfunctions associated with mental illnesses are the result of disruptions within and between the c-ICNs. Since its inception, support for this model has been rapidly mounting within the ID-domain e.

Notably, to our knowledge, our lab was the first to validate this model with source-space electroencephalography EEG [ 60 ]. EEG non-invasively tracks and records electrophysiological signals generated by the brain [ 34 — 36 ]. Although traditionally used to assess activity in sensor-space, modern source-space algorithms e.

Further, although standard clinical EEGs typically limit the recording bandwidth to traditional frequency bands i. Russian scientists discovered eISFs over half a century ago, first in rabbits [ 64 , 65 ] and shortly thereafter in humans [ 66 ] but, due in large part to technological challenges, they have received little interest from the scientific and clinicical communities until recently [ 63 , 67 — 70 ]. Putatively engendered by a combination of neuronal and glial currents [ 63 , 68 , 71 — 76 ], eISFs have been shown in both cortical [ 65 , 66 , 77 ] and subcortical [ 76 , 78 — 82 ] tissues and are believed to coordinate large-scale ICN organization and long-range information exchange [ 68 , 83 — 91 ].

As such, treatments specifically targeting eISFs within core nodes of the triple network may address c-ICN dysfunction and offer clinical utility in the treatment of IDs. Although traditional frontline therapies i.

Closed-loop brain training of electrophysiological EEG signals, also known as EEG-neurofeedback EEG-NFB , is a non-invasive therapy aimed at modulating brain function by teaching individuals, via associative learning e.

However, proponents contend that evidence of differential EEG-learning i. That said, assessments of differential EEG-learning are complicated by a lack of standardized criteria for the determination of learning or a lack thereof [ ]. Advanced source-localization i. To our knowledge, this is the first randomized, double-blind, sham-controlled trial examining the potential effects of source-space ISF-NFB in an ID population. Furthermore, our relatively novel transdiagnostic approach heeds recent calls for a more pragmatic, ecologically valid clinical research [ — ].

We hypothesize that all groups will show clinical improvements via non-specific e. Specifically, we are interested in whether there is evidence for an association between changes in the primary PRO i. To assess the potential clinical effects of an additional 6 treatment sessions i. We hypothesize that additional sessions will provide additional benefits for both treatment groups. To explore whether any potential associations observed in Objective 2 can be extended to post 12 sessions and 1-month follow-up amongst the ISF1 and ISF2 groups.

Not applicable: no biological specimens will be collected, and all data is to be used solely in accordance with this trial. Our choice of sham-controls allows us to elucidate any potential specific e. To reach the widest possible audience, ID participants will be recruited via both posters placed around the city and targeted Facebook ads with an invitation to participate in a University of Otago mental health study.

Advertisements will direct potential participants to a webpage that will describe the trial and invite those interested to complete a short online form which will query basic information including first name, age, date of birth, sex, ethnicity, education level, handedness, mental health history, pregnancy status, presence of electronic implants i. Individuals who complete the online form and meet the basic qualifications will be contacted via email and asked to attend an in-person mental health interview at the University of Otago Hospital, Dunedin, New Zealand.

Those that agree will be provided directions to the lab and a digital copy of the 7-page participant information sheet PIS. A reminder text will be sent to potential participants on the day of their interview. Recruitment will continue until our target sample sizes are met and is expected to take 18—24 months.

Participants will be informed that they may withdraw at any time without giving a reason and that all data collected up to the point of withdrawal may be used in the final analyses. The MINI is a brief structured diagnostic interview, shown to be both valid and reliable, used to assess the 17 most common psychiatric disorders including MDD, suicidality, bipolar, panic disorder, agoraphobia, SOC, obsessive-compulsive disorder, PTSD, alcohol use disorder, substance use disorder, psychoses, anorexia, bulimia, binge-eating disorder, GAD, and anti-social personality disorder [ , ].

Those meeting the eligibility criteria will be enrolled into the study, have their anthropometric i. Participants will also be familiarized with the study equipment, procedures, and personnel.

Baseline assessments will take place on two separate occasions approximately 1-week apart with baseline 2 values used as reference. Duplicate baseline assessments will be performed to mitigate the influence of certain non-specific effects i.

All assessment sessions for a given subject will take place at approximately the same time of day and be led by a female research assistant. A reminder email and text will be sent to each participant one day prior to and on the day of the assessment sessions, respectively.

Adherence to lifestyle restrictions will be queried at the beginning of each session with any breaches recorded. In cases of serious breaches e. Together, these standardization procedures are in line with current recommendations for neurophysiological data collection [ — ] and will help to control for variability in neurophysiological output stemming from important factors like circadian rhythms [ , ], gastric distention [ , , ], hydration levels [ , ], bladder distention [ , ], caffeine [ , ], nicotine [ , ] and alcohol [ , ].

All PROs English versions will be re-created in digital form via Qualtrics [ ] which will allow participants to complete them using an iPad during their EEG set-up. To prevent missing data, a visual alert will be generated if any queries on a given form have missing responses.

Research has indicated the electronic data collection increases the speed, accuracy, and user acceptability of the process [ — ]. The estimated total time to complete the battery of PROs is 20 min. The order of PRO administration will be standardized and based on questionnaire length i.

We chose the eyes-closed condition because it has been reported to improve EEG reliability [ , ]. The Electrooculography EOG will track vertical and horizontal eye movements. To help reduce impedances, subjects will be asked to arrive with non-braided, dry, clean i. During pacing, participants will be instructed to breathe through their nose at normal depth i.

Sham participants were offered active ISF-NFB upon their completion of the trial, thereby minimizing the potential of sham trial-associated participation barriers [ ] as well as addressing any potential ethical concerns of sham-only allocations. The randomization scheme will be generated by using the Web site Randomization. This tool is a valid randomization program utilized by clinical trial researchers. Randomization sequences were kept in the central office in sequentially numbered, sealed, opaque envelopes prepared by the lab member who generated the randomization scheme.

To ensure concealment, the block sizes will be known only by this lab member and not be disclosed to any of the researchers who have contact with the participants. TMP is responsible for participant enrolment and will assign participants to interventions following baseline assessments and upon arrival at their first ISF-NFB session.

This is a double-blind study whereby participants and raters will be unaware of group assignments. Treatment assignment will be disclosed to trial participants only upon their completion of the study. Training sessions will commence within 1-week after baseline 2 assessments.

To help reduce impedances, subjects were asked to arrive with non-braided, dry, clean i. Participants will attend three min sessions per week, every other day, over 4 consecutive weeks 12 sessions in total. Using a blunt need and syringe, the scalp will be mildly abraded prior to the application of an electrolyte gel beneath each electrode.

It should be noted that the purpose of the cool room and scalp abrasion is to mitigate contamination of the EEG signal by electrodermal i.

Participants will then be instructed to close their eyes, relax, stay awake, and listen to the sound being played. They will be informed that the sound they hear reflects that they are doing well.

Notably, no explicit strategies or instructions were given as, with few exceptions [ ], implicit strategies have been shown to produce better outcomes [ — ]. These ROIs were selected because, as outlined in the introduction, they are considered key cortical nodes within the core RSNs which are consistently found to be disrupted in ID populations.

For a complete list of targeted voxels for this trial, see Additional files 1 and 2. Targeted regions-of-interest ROIs. Note: red dot indicates salience network SN , and blue dot indicates the default mode network DMN node. Manual, rather than automated, thresholding was chosen as it has been reported to lead to better EEG-learning [ , , , ].

Importantly, this type of control allows matching of rewards and performance across sham and genuine conditions, thereby controlling as much as possible the learning context and degree of motivation [ ] while theoretically severing the operant conditioning aspect of EEG-NFB. Additionally, it has been reported that training effects are more robust when the clinician is present [ ], therefore, irrespective of group assignment, the trainer will be present for the duration of all sessions.

Materials: Describe any physical or informational materials used in the intervention, including those provided to participants or used in intervention delivery or training of intervention providers.

Provide information on where the materials can be accessed e. Subjects will be asked to arrive with non-braided, clean, dry hair. An appropriately sized Comby EEG cap will be affixed to the head and, using a blunt need and syringe, the scalp will be mildly abraded just prior to the application of the electrolyte gel beneath each electrode.

For each category of intervention provider e. Describe the modes of delivery e. Describe the type s of location s where the intervention occurred, including any necessary infrastructure or relevant features. Describe the number of times the intervention was delivered and over what period of time including the number of sessions, their schedule, and their duration, intensity or dose.

If the intervention was planned to be personalized, titrated or adapted, then describe what, why, when, and how. If the intervention was modified during the study, describe the changes what, why, when, and how.

Planned: If intervention adherence or fidelity was assessed, describe how and by whom, and if any strategies were used to maintain or improve fidelity, describe them.

All post-treatment assessments and procedures will be identical to those performed at baseline. Flow chart of enrollment, assessments, and interventions.

Participants will be advised that they were able to withdraw at any time without giving a reason or may be withdrawn by the lead investigator if they 1 experience significant adverse effects that were deemed detrimental to their well-being or 2 are unable to adhere to protocol e. We will attempt to mitigate adherence issues via automated email and text message reminders sent on the day of each training session.

Once enrolled, every reasonable effort will be made to follow participants throughout the entirety of the study period via ongoing email and text messaging correspondence. In the event of premature discontinuation of the study for any reason, participants will be made aware that all data collected up to the point of withdrawal may be used for analyses.

Participants were asked to maintain any current first-line mental health therapies e. Any changes or introductions of first-line therapies e. In the unlikely event of injury, participants will be eligible to apply for compensation from the Accident Compensation Corporation ACC of New Zealand just as they would be if they were injured in an accident at work or at home. Although there are private providers abroad e.

Asia, North America, and Europe , should this trial provide evidence of efficacy, there is currently no access to this therapy within New Zealand. The central importance of PROs in clinical trials has been emphasized by both international health regulatory agencies and patients [ , ], therefore, the primary outcome of interest will be the HADS [ , ].

Additionally, the importance targeted EEG-learning assessments in NFB trials has been emphasized by researchers [ — ], therefore activity i. Primary outcome measures will be collected at baseline, post 6 sessions, post 12 sessions, and 1-month follow-up. The HADS has been repeatedly shown to be a reliable and valid tool across a variety of settings [ , , ]. There is some debate with respect to whether the HADS is best assessed via the total item score [ — ] or two 7-item subscale anxiety and depression scores [ , , , ].

Further, source-localization software can locate the probable generators i. Non-EEG i. F11, FT11, F12, and FT12 channels will then be removed prior to manual co-registration used to match the coordinates of the 60 remaining channels to the realistic Boundary Element Model MNI head model. Of note, the four EEG channels selected for removal lack locations in the MNI coordinate file, thereby precluding subsequent pre-processing.

The data will then be truncated to retain only the middle s of the time-series, and the PREP pipeline version 0. This pipeline has been used previously for evoked potentials and resting-state EEG data [ , ]. Finally, bad ICs will be removed, noisy channels interpolated, and the data 0. Overview of EEG pre-processing pipeline. To allow for 2 complete cycles of the lowest frequency of interest i. Using the MNI Montreal Neurological Institute, Canada template, eLORETA produces an inverse solution space consisting of cortical grey matter voxels at 5 mm resolution and has been shown to produce exact, zero-error localizations even in the presence of measurement and structured biological noise.

Statistical non-parametric mapping SnPM will be performed for each contrast using built-in voxel-wise randomization test permutations to calculate the empirical probability distribution for the max-statistic e. Furthermore, for each condition, log-CSDs were averaged across all voxels within a mm radius of the centre of mass MNI coordinates derived from previous literature [ ] of the targeted ROIs Fig.

This output was exported to Excel version and analysed in R version 4. Next, functional connectivity FC; i. Granger causality [ ] analyses. Regions-of-interest ROIs and their centre of mass coordinates. The IDAS-II is a valid and reliable item, trans-diagnostic PRO measure that uses a response scale ranging from 1 not at all to 5 extremely to assess 19 current past 2 weeks ID-related symptom domains including general depression 20 items , dysphoria 10 items , lassitude 6 items , insomnia 6 items , suicidality 6 items , appetite loss 3 items , appetite gain 3 items , well-being 8 items , ill temper 5 items , mania 5 items , euphoria 5 items , panic 8 items , social anxiety 6 items , claustrophobia 5 items , traumatic intrusions 4 items , traumatic avoidance 4 items , checking 3 items , ordering 5 items , and cleaning 7 items [ , ].

Notably, in contrast to the other domains, the general depression domain is a composite of all 10 items from the dysphoria domain, as well as 2 items each from the suicidality, lassitude, insomnia, appetite loss and well-being domains. Recently, severity mild, moderate, severe thresholds have been introduced for 12 of the subscales including general depression, dysphoria, lassitude, insomnia, suicidality, appetite loss, appetite gain, well-being, ill-temper, panic, social anxiety, and traumatic intrusions [ ].

The IUS is a valid and reliable item, transdiagnostic PRO measure that assesses the degree to which an individual considers the possibility of a negative event occurring unacceptable, irrespective of its probability of occurrence [ , ]. Intolerance of uncertainty IU is a common trait shared across the ID spectrum [ — ]. Repetitive negative thinking i. Heart rate variability HRV is the phenomenon of cyclical beat-to-beat changes in the interbeat interval i.

RR interval , the dynamics of which can give insight into cardiac autonomic function [ ]. This has significant clinical implications considering that cardiovascular disease is the leading cause of mortality in people with mental illness [ 52 , , ]. HRV is typically measured via the standard time-domain i.

Pchip interpolation was chosen because appears to perform best across the spectrum of HRV metrics as it preserves the linear trend as well as the non-linear contributions in the R-R timeseries [ ].

Indices for both spontaneous and paced breathing conditions will be reported. Due to its novelty, there was no existing information around standard deviations for the measurements of interest.

Therefore, no formal sample size or power calculations were made. Importantly, due to the pilot nature of this trial, only potential efficacy or lack thereof can be established via statistical analyses. Between-group sham vs. For this analysis, we will use LORETA-Key software and a Bayesian model with random effects to allow for baseline differences and non-specific temporal effects between participants.

A sensitivity analysis will be carried out to compare this approach with an ANCOVA that includes a linear baseline adjustment. Regression methods will be used to explore the relationship between changes in the primary PRO subscales i. Within-group ISF1 and ISF2 comparisons between post-6 sessions and post sessions will be performed for all outcome measures.

The same model will be applied as in Objective 1 where random effects will now allow for post-6 session differences between participants. Within-group ISF1 and ISF2 comparisons between post sessions and 1-month follow-up will be performed for all outcome measures. This will use the same model as Objective 1 where random effects will now allow for post session differences between participants.

For all endpoints, responses were modelled assuming a normal distribution e. When normality assumptions were not met, appropriate transformations were performed. Additionally, potential endpoint covariates were examined e. Vague priors were used throughout. For all outputs, checks for the validity of assumptions regarding the residuals i.

Bayesian p -value will be performed. Not applicable: no interim analyses will be performed, and no stopping guidelines will be established. We will utilize complete-case analysis for all endpoints and objectives. Further, we will report the number and percentages of withdrawal in each of the groups. We will systematically monitor adverse effects from the therapy for the duration of the trial using the Discontinuation-Emergent Signs and Symptoms checklist DESS [ ] created, verbatim, in Qualtrics and completed by participants on an iPad during EEG set-ups in the interventional and post-interventional phases.

The DESS has been used for the assessment of treatment-related side-effects in ID populations [ , ] and, recently, has been employed to monitor adverse-effects specifically associated with NFB therapy [ ].

Participants may be withdrawn from the trial by the investigators, even without their request, in the event of serious adverse effects.

Participant paper files, including case-report-forms CRFs and MINI assessments, are to be kept in numerical order and stored in a locked room accessible only to the researchers. All data collected will be entered into Microsoft Excel version and double-checked for accuracy by the data analyst at the time of entry.

Participant data will be maintained for a period of not less than 10 years after the completion of the study. All information generated in this study will be considered highly confidential and is not to be shared with any persons not directly concerned with the study.

For de-identification purposes, participants will be assigned unique study numbers upon enrolment. All electronic records will be identified solely using assigned study numbers and stored locally in a password-protected database. All paper records will be stored on-site in a locked office accessible only to the researchers directly involved in the trial.

Furthermore, paper documents that contain personal identifiers i. The final trial dataset will be password protected and housed locally at the research lab. Other team members will be provided access to this dataset by TMP upon request. To ensure confidentiality, data dispersed to project team members will be blinded of any identifying participant information. The full protocol will be submitted for publication to a peer-reviewed, open-source journal prior to analyses commencement.

No more than 2 years following the final data collection, we will deliver the completed, de-identified dataset and statistical code to the appropriate data archive for sharing purposes in line with the scientific imperatives of increased transparency, reproducibility, and interpretation of trials. Not applicable: no coordinating centre or trial steering committee for this trial. Not applicable: no auditing of trial conduct will be performed.

Substantive protocol amendments which may impact on the conduct of the study including changes to the study objectives, design, population, sample sizes, or procedures will be agreed upon by the research team, updated in the trial registry, submitted to the ethics committee for approval, and updated on our online trial advertisements and web pages.

Every effort will be made to minimize the interval between the completion of data collection and release of study results. We estimate this process to take 12 months. Irrespective of magnitude or direction of effect, results from the study will be written up and submitted to international peer-reviewed scientific journals, presented at scientific conferences, and may form part of grant applications.

In addition, once compiled, all participants will be provided with a digital copy of the results. Approximately one in five New Zealanders is dealing with a mental illness at any given time with the majority of the population expected to experience psychopathology at some point in their lifetime [ 7 ]. A recent government inquiry by the New Zealand government has shed light on the shortcomings of current treatment and called for wider implementation of non-pharmaceutical approaches in treatment of mental health problems [ 7 ].

The implementation of safe, non-invasive neuromodulation techniques that have the potential to impact neuroplasticity within and between large-scale ICNs may offer new treatment opportunities for individuals who either do not want, respond to, or tolerate standard interventions.

Additionally, these techniques may serve as adjuncts to traditional treatments, potentially enhancing their efficacy. We believe targeting core ICNs via this novel therapy offers a promising new avenue in the treatment of IDs and other psychopathologies.

Recruitment efforts resumed on 15 June , however, due to budgetary and time restrictions imposed by the lockdown, we amended our protocol. Specifically, our recruitment goal for clinical participants was changed from 80 40 males and 40 females to 60 females.

Data collection is on track to be completed by the end of We are grateful to all the trial participants for their willingness and commitment to participate in this trial. Recruitment efforts resumed in June , however, due to time and staffing restrictions resulting from the lockdown, we amended our original protocol.

Specifically, our trial recruitment goal was changed from 40 males and 40 females to 60 females. Additionally, rather than multiple PROs i.

Finally, electrodermal activity EDA assessment was removed due to equipment malfunction during testing. All amendments occurred prior to the start of data analyses. TMP conceived of the study and drafted the protocol. All authors contributed to the refinement of the trial protocol and provided feedback on the protocol manuscript.

The authors read and approved the final manuscript. This sponsor has no role in the study design, collection, management, analysis, interpretation of data, or dissemination of results.

Written, informed consent to participate will be obtained from all participants. Examples of the participant information and informed consent forms can be provided upon request. He created the ISF-NFB software programs for this trial, provided guidance to the principal investigator in their utilization, and participated in editing of the final version of the manuscript.

MS did not participate in the trial conceptualisation, design, implementation, or analyses. All other authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Published online Nov Tyson M. Perez , 1, 2 Paul Glue , 2 Divya B. Adhia , 1 Muhammad S. Niazi , 3 Calvin K. Young , 8 and Dirk De Ridder 1. Divya B. Muhammad S. Imran K. Calvin K. Author information Article notes Copyright and License information Disclaimer.

Perez, Email: zn. Corresponding author. Received May 14; Accepted Oct The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Associated Data Supplementary Materials Additional file 1. MCC voxelsR1. Additional file 2. PCC voxelsR1. Supplementary Information The online version contains supplementary material available at Keywords: Internalizing disorders, Generalized anxiety disorder, Major depressive disorder, Social anxiety disorder, EEG neurofeedback, Infraslow fluctuations, Triple network, Salience network, Default mode network, Central executive network, Randomized controlled trial.

Introduction Background and rationale Mental disorders are one of the most common causes of morbidity and mortality worldwide [ 1 ] with rates markedly increasing in recent years [ 2 — 6 ]. Secondary research questions Objective 3 To assess the potential clinical effects of an additional 6 treatment sessions i. Objective 5 To explore whether any potential associations observed in Objective 2 can be extended to post 12 sessions and 1-month follow-up amongst the ISF1 and ISF2 groups.

Methods: participants, interventions, and outcomes Study population and setting Our target population is adult females meeting the DSM-5 criteria for one or more IDs of interest i. Eligibility criteria Inclusion criteria: Able to give informed consent. Any externalizing disorder e. Additional consent provisions for collection and use of participant data and biological specimens Not applicable: no biological specimens will be collected, and all data is to be used solely in accordance with this trial.

Explanation for the choice of comparators Our choice of sham-controls allows us to elucidate any potential specific e. Recruitment To reach the widest possible audience, ID participants will be recruited via both posters placed around the city and targeted Facebook ads with an invitation to participate in a University of Otago mental health study.

Who will take informed consent? Baseline assessments Baseline assessments will take place on two separate occasions approximately 1-week apart with baseline 2 values used as reference.

Sequence generation The randomization scheme will be generated by using the Web site Randomization. Concealment mechanism Randomization sequences were kept in the central office in sequentially numbered, sealed, opaque envelopes prepared by the lab member who generated the randomization scheme.

Implementation enrolment and assignment TMP is responsible for participant enrolment and will assign participants to interventions following baseline assessments and upon arrival at their first ISF-NFB session. Who will be blinded? Procedure for unblinding if needed Treatment assignment will be disclosed to trial participants only upon their completion of the study. Intervention descriptions Training sessions will commence within 1-week after baseline 2 assessments.

Open in a separate window. Item number Item Description 1. Brief name Provide the name or a phrase that describes the intervention. Why Describe any rationale, theory, or goal of the elements essential to the intervention. Further, communication within and between core-ICNs has been found to be disrupted in internalizing disorder ID populations.

What Materials: Describe any physical or informational materials used in the intervention, including those provided to participants or used in intervention delivery or training of intervention providers. Free, open-source software Audacity. The trainer will remain present for the duration of all sessions to monitor the EEG.

Who provided For each category of intervention provider e. How Describe the modes of delivery e. Where Describe the type s of location s where the intervention occurred, including any necessary infrastructure or relevant features.

When and how much Describe the number of times the intervention was delivered and over what period of time including the number of sessions, their schedule, and their duration, intensity or dose. Participants will attend three min sessions per week over 4 consecutive weeks 12 sessions in total. Tailoring If the intervention was planned to be personalized, titrated or adapted, then describe what, why, when, and how. Thresholds will be manually adjusted, as needed, to maintain the pre-specified feedback success rate i.

Modifications If the intervention was modified during the study, describe the changes what, why, when, and how. Not applicable. This is a protocol. How well Planned: If intervention adherence or fidelity was assessed, describe how and by whom, and if any strategies were used to maintain or improve fidelity, describe them. Protocol adherence will be monitored by the trainer.

Attempts will be made to mitigate adherence issues via automated email and text message reminders sent on the day of each training session. Actual: If intervention adherence or fidelity was assessed, describe the extent to which the intervention was delivered as planned.

Table 2 Schedule of enrollment, interventions, and assessments. Criteria for discontinuing or modifying allocated interventions Participants will be advised that they were able to withdraw at any time without giving a reason or may be withdrawn by the lead investigator if they 1 experience significant adverse effects that were deemed detrimental to their well-being or 2 are unable to adhere to protocol e.

Strategies to improve adherence to interventions We will attempt to mitigate adherence issues via automated email and text message reminders sent on the day of each training session.

Plans to promote participant retention and complete follow-up Once enrolled, every reasonable effort will be made to follow participants throughout the entirety of the study period via ongoing email and text messaging correspondence.

Relevant concomitant care permitted or prohibited during the trial Participants were asked to maintain any current first-line mental health therapies e. Provisions for post-trial care In the unlikely event of injury, participants will be eligible to apply for compensation from the Accident Compensation Corporation ACC of New Zealand just as they would be if they were injured in an accident at work or at home.

Inventory of depression and anxiety symptoms — second version IDAS-II The IDAS-II is a valid and reliable item, trans-diagnostic PRO measure that uses a response scale ranging from 1 not at all to 5 extremely to assess 19 current past 2 weeks ID-related symptom domains including general depression 20 items , dysphoria 10 items , lassitude 6 items , insomnia 6 items , suicidality 6 items , appetite loss 3 items , appetite gain 3 items , well-being 8 items , ill temper 5 items , mania 5 items , euphoria 5 items , panic 8 items , social anxiety 6 items , claustrophobia 5 items , traumatic intrusions 4 items , traumatic avoidance 4 items , checking 3 items , ordering 5 items , and cleaning 7 items [ , ].

Intolerance of uncertainty scale — Short form IUS The IUS is a valid and reliable item, transdiagnostic PRO measure that assesses the degree to which an individual considers the possibility of a negative event occurring unacceptable, irrespective of its probability of occurrence [ , ].

Statistical considerations Objective 1 Between-group sham vs. Objective 2 Regression methods will be used to explore the relationship between changes in the primary PRO subscales i. Objective 3 Within-group ISF1 and ISF2 comparisons between post-6 sessions and post sessions will be performed for all outcome measures.

Objective 4 Within-group ISF1 and ISF2 comparisons between post sessions and 1-month follow-up will be performed for all outcome measures. The percentage in ROPE indexes the magnitude of an effect where the ROPE is the range of effect size values considered to be practically equivalent to the null [ , ].

Interim analyses Not applicable: no interim analyses will be performed, and no stopping guidelines will be established. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data We will utilize complete-case analysis for all endpoints and objectives.

Adverse event reporting and harms We will systematically monitor adverse effects from the therapy for the duration of the trial using the Discontinuation-Emergent Signs and Symptoms checklist DESS [ ] created, verbatim, in Qualtrics and completed by participants on an iPad during EEG set-ups in the interventional and post-interventional phases.

Data management and processing Participant paper files, including case-report-forms CRFs and MINI assessments, are to be kept in numerical order and stored in a locked room accessible only to the researchers.

Confidentiality All information generated in this study will be considered highly confidential and is not to be shared with any persons not directly concerned with the study. Access to data The final trial dataset will be password protected and housed locally at the research lab. Plans to give access to the full protocol, participant level-data and statistical code The full protocol will be submitted for publication to a peer-reviewed, open-source journal prior to analyses commencement.

Oversight and monitoring Composition of the coordinating Centre and trial steering committee Not applicable: no coordinating centre or trial steering committee for this trial. Frequency and plans for auditing trial conduct Not applicable: no auditing of trial conduct will be performed.

Plans for communicating important protocol amendments to relevant parties e. Dissemination policy Every effort will be made to minimize the interval between the completion of data collection and release of study results. Discussion Approximately one in five New Zealanders is dealing with a mental illness at any given time with the majority of the population expected to experience psychopathology at some point in their lifetime [ 7 ].

Supplementary Information Additional file 1. Acknowledgements We are grateful to all the trial participants for their willingness and commitment to participate in this trial.

Consent for publication Examples of the participant information and informed consent forms can be provided upon request.

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Transdiagnostic, brain-Centred approaches to psychopathology: a study in Internalzing disorders. Dunedin: University of Otago; Pascual-Marqui RD. Methods Find Exp Clin Pharmacol. Clin EEG Neurosci. No significant differences were found for hearing loss between males and females, as measured by the loss in decibels dB HL at the tinnitus frequency.

Participants were requested to refrain from alcohol consumption 24 hours prior to recording and from caffeinated beverages on the day of recording.

Subjective depression was assessed with the Beck Depression Inventory-revised BDI—II , a item self-report instrument with good psychometric properties [59].

This study was approved by the local ethical committee Antwerp University Hospital and was in accordance with the declaration of Helsinki.

Patients gave oral informed consent before the procedure. The EEG was obtained as a standard procedure for diagnostic and neuromodulation treatment purposes. EEG recordings were obtained in a fully lighted room with each participant sitting upright on comfortable chair.

The actual recording lasted approximately 5 min. Data were resampled to Hz, band-pass filtered fast Fourier transform filter to 2—44 Hz and subsequently transposed into Eureka! Software [60] , plotted and carefully inspected for manual artifact-rejection. All episodic artifacts including eye blinks, eye movements, teeth clenching, body movement, or ECG artifact were removed from the stream of the EEG.

In addition, an independent component analysis ICA was conducted to further verify if all artifacts were excluded. To investigate the effect of possible ICA component rejection we compared the power spectra in two approaches: 1 after visual artifact rejection only before ICA and 2 after additional ICA component rejection after ICA.

To test for significant differences between the two approaches we performed a repeated-measure ANOVA, considering mean band power as within-subject variable and groups unilateral vs. The mean power in delta 2—3. Therefore, we continue by reporting the results of ICA corrected data. Average Fourier cross-spectral matrices were computed for bands delta 2—3.

Recordings were made in similar circumstances, i. None of these subjects were known to suffer from tinnitus or hearing loss. Data were resampled to Hz, band-pass filtered fast Fourier transform filter to 2—44 Hz. The data were cleaned-up in a similar way to the tinnitus patients by manual artifact rejection and ICA.

Again to investigate the effect of possible ICA component rejection we compared the power spectra in two approaches: 1 after visual artifact rejection only before ICA and 2 after additional ICA component rejection after ICA. To test for significant differences between the two approaches we performed a repeated-measure ANOVA, considering mean band power as within-subject variable.

Standardized low-resolution brain electromagnetic tomography sLORETA was used to estimate the intracerebral electrical sources that generated the scalp-recorded activity in each of the eight frequency bands [61]. Further sLORETA validation has been based on accepting as ground truth the localization findings obtained from invasive, implanted depth electrodes, in which case there are several studies in epilepsy [70] , [71] and cognitive ERPs [72]. It is worth emphasizing that deep structures such as the anterior cingulate cortex [73] , and mesial temporal lobes [74] can be correctly localized with this method.

However, any measure of dependence is highly contaminated with an instantaneous, non-physiological contribution due to volume conduction and low spatial resolution Pascual-Marqui, a. Therefore Pascual-Marqui, b introduced a new technique i. Hermitian covariance matrices that removes this confounding factor considerably. As such, this measure of dependence can be applied to any number of brain areas jointly, i.

Measures of linear dependence coherence between the multivariate time series are defined. The measures are expressed as the sum of lagged dependence and instantaneous dependence. The measures are non-negative, and take the value zero only when there is independence of the pertinent type and are defined in the frequency domain: delta 1—3. Based on this principle lagged linear connectivity was calculated. Regions of interest were defined based on previous brain research on tinnitus see table 2 for overview and the present findings based on the source analysis e.

In order to identify potential differences in brain electrical activity between groups, sLORETA was then used to perform voxel-by-voxel between-condition comparisons of the current density distribution. As explained by Nichols and Holmes, the SnPM methodology does not require any assumption of Gaussianity and corrects for all multiple comparisons [75]. We performed one voxel-by-voxel test comprising 6, voxels each for the different frequency bands.

The log-transformed electric current density was averaged across all voxels belonging to the region of interest, respectively left and right primary auditory cortex BA40 and BA41 and left and right secondary auditory cortex BA21 and BA22 separately for the gamma frequency band.

Wilks' Lambda for the frequency bands was used with the respective region of interest i. A Bonferroni correction was applied for multiple comparisons. The aim was to verify whether gender significantly contributed to the model. In order to verify whether the findings obtained are not related to artifacts i. To summarize the data and because spectra from all electrodes demonstrated similar shape and scale, we averaged the log transformed spectra of all 4 scalp electrodes for each subject.

We then averaged these individual spectra to one spectrum for respectively male controls, female controls, male tinnitus patients and female tinnitus patients. In addition also the brain topographies for beta 1, beta2, and beta3 were calculated to further detect possible artifacts. Competing Interests: The authors have declared that no competing interests exist.

Funding: These authors have no support or funding to report. PLoS One. Published online Feb Thomas Koenig, Editor. Author information Article notes Copyright and License information Disclaimer.

Received Sep 23; Accepted Jan 4. Copyright Vanneste et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

Abstract Background Tinnitus refers to auditory phantom sensation. Methodology The objective of this study was to verify whether the activity and connectivity of the resting brain is different for male and female tinnitus patients using resting-state EEG.

Introduction Subjective tinnitus is a condition in which a patient perceives an auditory phantom sound that can take the form of ringing, buzzing, roaring or hissing in the absence of an external sound [1]. Source localization A comparison was made between tinnitus patients and a control group. Open in a separate window. Figure 1. Figure 2. Figure 3.

Figure 4. Figure 5. Region of interest analysis 1. Figure 6. Region of interest analysis for the Orbitofrontal cortex for respectively beta1 and beta2 frequency band log-transformed current density. Figure 7. Region of interest analysis for the left and right primary and secondary auditory cortex for gamma band frequency log-transformed current density. Hierarchical regression analyses In order to investigate the relative importance of both gender and BDI on the OFC for respectively beta1 and beta2, hierarchical regression analyses with OFC for respectively beta1 and beta2 as the dependent variable and BDI and gender as independent variables were conducted.

Figure 8. Brain topography and Power Spectra To verify whether the obtained results in the OFC are not artifact related both brain topographies and a power spectrum analysis was conducted. Figure 9. Figure Discussion This study investigated gender-specific neural correlates of tinnitus. Table 1 Patients' characteristics.

Gender Females Males p-values Age EEG recording EEG recordings were obtained in a fully lighted room with each participant sitting upright on comfortable chair. Source localization Standardized low-resolution brain electromagnetic tomography sLORETA was used to estimate the intracerebral electrical sources that generated the scalp-recorded activity in each of the eight frequency bands [61].

Table 2 Regions of Interest. Statistical analysis In order to identify potential differences in brain electrical activity between groups, sLORETA was then used to perform voxel-by-voxel between-condition comparisons of the current density distribution. Region of interest analysis The log-transformed electric current density was averaged across all voxels belonging to the region of interest, respectively left and right primary auditory cortex BA40 and BA41 and left and right secondary auditory cortex BA21 and BA22 separately for the gamma frequency band.

Footnotes Competing Interests: The authors have declared that no competing interests exist. References 1. The neuroscience of tinnitus. Trends Neurosci. Heller AJ. Classification and epidemiology of tinnitus. Otolaryngol Clin North Am. New York: Guilford; Lazarus RS, Folkman S.

Stress, appraisal, and coping. New York: Springer; The impact of perceived tinnitus severity on health-related quality of life with aspects of gender. Noise Health. Sex differences in emotional and psychophysiological responses to musical stimuli. Int J Psychophysiol.

The emergence of gender differences in depression during adolescence. Psychol Bull. Gender differences in the relationship between emotional regulation and depressive symptoms. Cognitive Therapy and Research. Gender differences in neural correlates of recognition of happy and sad faces in humans assessed by functional magnetic resonance imaging. Neurosci Lett.

Sex differences in the neural basis of emotional memories. Sex-related differences in neural activity during emotion regulation. Sex specificity of ventral anterior cingulate cortex suppression during a cognitive task.

Hum Brain Mapp. Abnormal resting-state cortical coupling in chronic tinnitus. BMC Neurosci. Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.

J Neurol Neurosurg Psychiatry. Lateralization of functional magnetic resonance imaging fMRI activation in the auditory pathway of patients with lateralized tinnitus.

Structural brain changes in tinnitus. Cereb Cortex. On females' lateral and males' bilateral activation during language production: a fMRI study.

Activation in primary auditory cortex during silent lipreading is determined by sex. Audiol Neurootol. Functional sex differences in human primary auditory cortex. Age- and gender-related differences in the cortical anatomical network.

J Neurosci. Sex-related differences in amygdala functional connectivity during resting conditions. Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain. Treatment of chronic tinnitus with repeated sessions of prefrontal transcranial direct current stimulation: outcomes from an open-label pilot study. Kropotov JD.

Quantitative EEG, event-related potentials and neurotherapy. San Diego: Academic Press; Gender differences in clinical characteristics in a naturalistic sample of depressive outpatients: The Leiden Routine Outcome Monitoring Study. J Affect Disord. Mol Psychiatry. Left temporal low-frequency rTMS for the treatment of tinnitus: clinical predictors of treatment outcome - a retrospective study.

Eur J Neurol. Comparator and non-comparator mechanisms of change detection in the context of speech—an ERP study. Functional-anatomic correlates of memory retrieval that suggest nontraditional processing roles for multiple distinct regions within posterior parietal cortex. Distributed and antagonistic contributions of ongoing activity fluctuations to auditory stimulus detection. The neural correlates of tinnitus-related distress. Amygdalohippocampal involvement in tinnitus and auditory memory.

Acta Otolaryngol. Sensory gating in the human hippocampal and rhinal regions: regional differences. Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia. Am J Psychiatry. Dissociation in prefrontal cortex of affective and attentional shifts. Frontal brain asymmetry and emotional reactivity: a biological substrate of affective style.

Damasio AR. The somatic marker hypothesis and the possible functions of the prefrontal cortex. Emotional responses to pleasant and unpleasant music correlate with activity in paralimbic brain regions. Nat Neurosci. Reduced startle reflex and aversive noise perception in patients with orbitofrontal cortex lesions.

Gender differences in the cognitive control of emotion: An fMRI study. How the orbitofrontal cortex contributes to decision making - a view from neuroscience. Prog Brain Res. Audiological and psychological characteristics of a group of tinnitus sufferers, prior to tinnitus management training. Br J Audiol.

Sex differences in the time course of emotion. Craig AD. Interoception: the sense of the physiological condition of the body. Curr Opin Neurobiol. Neural systems supporting interoceptive awareness. Beauregard M. Mind does really matter: evidence from neuroimaging studies of emotional self-regulation, psychotherapy, and placebo effect. Prog Neurobiol.

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