fNIRS Neurofeedback in Highly Impulsive Participants With ROI Regions DLPFC and IFG
Condition: Impulsivity
MeSH terms: Impulsive Behavior
Study type: Interventional

Summary: 
      The aim of the following study is to investigate which is the best region of interest (ROI)
      for a functional near-infrared spectroscopy (fNIRS)-based neurofeedback (NF) training for
      highly-impulsive individuals (and consequently also patients with
      attention-deficit/hyperactivity disorder, ADHD): the dorsolateral prefrontal cortex (DLPFC)
      or the inferior frontal gyrus (IFG). Generally, NF trainings aim to improve the
      neurophysiological as well as cognitive-behavioral deficits observed in many neuropsychiatric
      disorders and were shown to constitute an effective complementary treatment option for
      patients with ADHD. Some previous studies used the DLPFC as a ROI for NF training, while
      others focused on the IFG as the main target region. However, so far, no study has directly
      compared the effectiveness of NF trainings targeting the DLPFC vs. IFG using the same
      protocol or the specificity of regulation efforts between these two areas using fNIRS.
      Therefore, the aim of the current study is to compare the effectiveness of fNIRS-NF using the
      DLPFC as a ROI with fNIRS-NF using the IFG as a ROI in a randomized controlled study design
      with highly-impulsive, healthy participants.

      Furthermore, the investigators aim to test the effect of fNIRS-NF training in the context of
      stress. Previous studies reported that there is a strong connection between ADHD and stress.
      However, the effect of fNIRS-NF training for the adaptation to stressful situations is
      uncertain.

      To this end, the investigators will assess the brain activity of participants before and
      after an fNIRS-NF training period during performance of a Go/NoGo task, an n-back task and
      The Trier Social Stress Test (TSST). It is hypothesized that both trainings will be
      successful in reducing impulsive behavior; however, in the pre/post testing, specific effects
      of fNIRS-based NF of the DLPFC are expected on working memory function and of fNIRS-based NF
      of the IFG on inhibitory control (Go/NoGo task). Correlations between both functions and
      impulsive symptoms will give an indication which training ROI may be more promising for the
      treatment of (specific subgroups of) ADHD. Correlations between regulation of different
      training ROIs will indicate the specificity of feedback regulation of circumscribed cortical
      areas.
    

Detailed description: 
      Aims:

      The investigators will assess the effects - and specificity - of two fNIRS-based NF
      protocols, one targeting the DLPFC and one targeting the IFG. Both groups will also be
      compared to a "sham" training group with regulation of the fNIRS signal outside of the
      frontal lobes. Pre/post testing will be conducted in all three groups, i.e., measures of
      brain activity, cognition and impulsive behavior will be obtained before the start of the NF
      training phase as well as following the last training session. Thereby, a Go/Nogo task and an
      n-back task will be applied to evaluate training-related changes in brain activity and
      neuropsychological performance. The study population will be highly impulsive (healthy)
      individuals, who were previously found to show a reduced DLPFC and IFG activity (similar to
      patients with ADHD), and the investigators expect their DLPFC and IFG function to increase
      after fNIRS-NF training. Our hypothesis is that both active NF groups (DLPFC and IFG) will
      improve more than the placebo (sham training) group on all relevant measures. Thereby,
      specific advantages are expected in the DLPFC group for working memory data (n-back task) and
      in the IFG group for measures of inhibitory control (Go/Nogo task). Further, the
      investigators will test the effect of fNIRS-NF on the stress response using the TSST as a
      standardized stress test. It is hypothesized that fNIRS-NF training is also effective in
      reducing stress by strengthening stress-related regulation (that has also been related to the
      frontal lobe).

      It is hypothesized that both trainings will be successful in reducing impulsive behavior;
      however, in a pre/post testing, specific effects of fNIRS-based NF of the DLPFC on working
      memory function and of fNIRS-based NF of the IFG on inhibitory control is expected.
      Correlations between both functions and impulsive symptoms will give an indication which
      training ROI may be more promising for the treatment of (specific subgroups of) ADHD.
      Correlations between regulation of different training ROIs will indicate the specificity of
      feedback regulation of circumscribed cortical areas.

      Functional near-infrared spectroscopy (fNIRS):

      An fNIRS system (ETG-4000, Hitachi Medical Corporation, Japan) will be used to measure
      hemodynamic responses within the prefrontal cortex (PFC).

      All experiments will be conducted at the Department of Psychiatry and Psychotherapy,
      University of Tübingen (Calwerstraße 14/Osianderstraße 24, 72076 Tübingen). All
      medical-technical devices are CE certified and approved for application in patients and will
      only be used according to their approved purpose by persons who have the knowledge and
      experience to operate, apply and maintain the devices.

      Neurofeedback:

      One NF session comprises 2 feedback blocks each lasting 12 min and one transfer block lasting
      8 min. A feedback block consists of 12 regulation trials. One regulation trial consists of 20
      s resting time and 30 s regulation time. The task is to increase or decrease the hemodynamic
      activity in the DLPFC or IFG (or, for the sham control group, 4 channels of the temporal
      cortex, which is putatively not involved in impulsivity/ADHD symptomatology; furthermore, in
      an unpublished pilot study, these 4 channels were found to be inactive during a Stroop task
      involving cognitive control functions), with 50% activation trials and 50% deactivation
      trials, which were presented in random order. As a feedback of hemodynamic brain activation,
      a ball is shown to the participant on a screen, moving from left to right and depicting
      concentration changes in oxygenated hemoglobin by moving below or above a line in the middle
      of the screen. An arrow in the middle of the screen indicates if activation (pointing
      upwards) or deactivation (pointing downwards) is expected on a given trial. In activation
      trials, the concentration of oxygenated hemoglobin should increase in comparison to the
      baseline, in deactivation trials it should decrease. At the end of a successful trial (the
      ball moved in the expected direction for at least 7 s of the last 15 s regulation time), a
      rewarding feedback ("Gut gemacht, weiter so!", which is German for "Well done, continue like
      this!") is shown on the screen. A transfer block consists of 8 regulation trials in which the
      moving ball is not shown, but the reward at the end of the trial still indicates whether the
      participant was successful. The transfer blocks are included in order to facilitate transfer
      of the learned regulation strategies into everyday life.

      Study population:

      Participants will be recruited from the local student population via advertisements/email and
      from existing databases. An online system will be used to have potential participants fill
      out the ASRS in order to classify them as highly- or low-impulsive. During this online
      screening procedure, they confirm with a button press that they read the study information
      and the informed consent and that they agree with the usage of their data. They "continue" by
      a further button press and will be informed about their rights. Appropriate potential
      participants (highly-impulsive healthy subjects with ASRS scores >15 but <23) are contacted
      again for a study appointment. The complete study information, informed consent and data
      safety form will be sent to the potential participant at that time. When they arrive for the
      actual laboratory appointment, they will again receive explanations on all procedures and
      possible risks verbally and in written form. They are included in the study, when they give
      their written informed consent.

      Sample Size Estimation:

      The proposed project is planned as a randomized, controlled trial and comprises a total of 60
      participants divided into an IFG-, a DLPFC and a placebo training group receiving either
      IFG-based, DLPFC-based or a sham (temporal cortex) NF control training. Based on the effect
      sizes of NF interventions typically observed in patients with ADHD (around d=0.8 for
      attention-related symptom improvements, as compared to different control groups including
      waiting list, EMG biofeedback and cognitive training; see e.g. Arns, de Ridder, Strehl,
      Breteler & Coenen, 2009), subgroup sample sizes of n=20 would be the result of a formal power
      calculation, with a pre-defined α of 0.05 and an intended power of at least 80%. Closely
      related to the currently planned training protocol, recent own data confirm effect sizes of
      at least 0.8 for pre-post comparisons within a control group design. In detail, following
      eight training sessions with a frontal-lobe focused fNIRS-based NF training, highly-impulsive
      subjects showed positive changes in both target cognitive measures (standard deviation of RTs
      in a stop signal task) and cortical activation (left DLPFC) that were significantly stronger
      than in an EMG-based control training group (Hudak et al., 2017) with effect sizes of dcorr =
      0.981 and 1.61, respectively (formula according to Klauer (2001) for pre-post control design
      studies). Taken together, and relying on the more conservative estimation of NF effects on
      the symptom level itself (see above), a sample size of n=20 per group and treatment arm thus
      seems to be adequate for the different aims and questions of the proposed study.

      Risks and side effects:

      FNIRS: No medical risks are associated with a fNIRS recordings; when laser diodes are used,
      which is the case in the present study, no significant tissue heating occurs. In order to
      avoid any accidental problems, all possible precautions will be taken. Guidelines and
      protocols on how to handle the measurement applications (e.g., comfortable adjustment of the
      NIRS cap) will be followed strictly as suggested by experienced laboratories. Moreover, the
      experimenters will work under close supervision of Dr. Ann-Christine Ehlis.

      FNIRS-based NF: Risks associated with fNIRS-based NF treatment are few, rare, and quickly
      remediable. For individuals who are highly sensitive or susceptible, fNIRS-based NF may
      precipitate a migraine headache (muscle tension induced), hot flash, or mild anxiety
      (performance induced). Potential problems can be minimized and averted by obtaining an
      adequate medical history prior to treatment. Side effects are typically mild, transient, and
      quickly remediable allowing participants to continue with treatment.

      Data Privacy:

      All experimenters are bound to professional discretion. Medical doctoral students / master
      students potentially involved in the project will get detailed explanations of all procedures
      and will sign a contract for applying these guidelines. The confidential treatment of the
      data according to the data privacy act is guaranteed. As data is encoded on acquisition, it
      is not possible to assign published results to individuals. Recordings enabling a
      re-identification are locked and only accessible to staff members (for further details, see
      below). The following rules will be applied for handling the data.

      Data acquisition and storage:

      Data will be stored by using codes. These pseudonyms will be created for each participant
      (german: "Pseudonymisierung"). The codes are composed out of the name of the used paradigm
      and the running number of the participant.

      There will be only three forms with the participants' name on them. First, participants will
      write their name, date of birth and signature on the consent form. Second, the experimenter
      will note down the participants name, date of birth and study code on the protocol form. This
      protocol will be the only way to link a participant's study code with her/his identity.
      Third, participants will sign a form for having received participation fee. All three
      documents will be stored apart from the other study documents in a lockable cupboard. The
      keys for this cupboard and for the room will be accessible solely with a licence signed by
      Dr. A.-C. Ehlis, head of the research group "Psychophysiology and Optical Imaging" at the
      Department of Psychiatry and Psychotherapy in Tuebingen.

      The psychometric questionnaires will be stored in a cupboard in a lockable room. Only
      participants' study code is noted down on these questionnaires. The keys for the room will
      also be accessible solely with a licence signed by Dr. A.-C. Ehlis. These documents will be
      destroyed after ten years. Furthermore, the questionnaire data and participants' study codes
      will be entered into a data matrix of the programs Excel or SPSS for further analyses. The
      imaging data are also labelled with participants study codes.

      The online questionnaire will be constructed and distributed using SoSciSurvey software.
      SoSciSurvey saves all data on a German server (located in Munich). SoSciSurvey does not share
      any data with third parties, does not save IP addresses and deletes all data if the project
      manager has not logged into the system for three months. All data are encrypted during data
      transfer. Thus, SoSciSurvey offers a very high security standard. Following the online
      assessment period, the data will be downloaded and stored on a password-protected hard disk
      of the University Hospital Tübingen (Psychophysiology & Optical Imaging group). All data will
      then be deleted from the SoSciSurvey server.

      Data analysis:

      The coded data will be analyzed and results will be published in specific scientific
      journals. There will be no possibility to deduce information about single participants from
      these results.

      FNIRS data will be analyzed with the software package implemented in the ETG-4000 (Topo
      software by Hitachi Medical Co., Japan) as well as MATLAB (The MathWorks Inc.), a commercial
      software applied to the offline analysis of the change in haemoglobin concentration.
      Additionally, statistical analyses will be conducted with the software packages Excel
      (Microsoft inc.) and SPSS. For statistical analysis, mainly ANOVAs for repeated measures and
      correlation analyses will be applied. Post-hoc comparisons will be conducted using t-tests
      for matched or independent samples as well as correlation analyses.
    

Intervention name(s): fNIRS-Neurofeedback
Intervention type(s): Device
Intervention description(s): Neurofeedback of cortical oxygenation in 4 channels (2 left hemisphere, 2 right hemisphere); 8 training sessions, each session includes 2 feedback blocks (2*12 activation/deactivation trials) and one transfer block (8 activation/deactivation trials)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science