Clinical trial NCT04545294: Theta tACS During Working Memory Training: A Pilot Study of the Effects on Negative Symptoms of Schizophrenia
Official title: Online Left-hemispheric Frontoparietal Theta In-phase tACS During Working Memory Training in Schizophrenia Patients: A Pilot Randomized Double-blind, Sham-controlled Study of the Effects on Negative Symptoms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Schizophrenia
Schizoaffective Disorder
Negative Symptoms
Working Memory Training
Psychosocial Impairment
Autonomic Imbalance
EEG
Keywords: Schizophrenia
Schizoaffective Disorder
Transcranial alternating current stimulation
Theta oscillatory rhythm
Theta Phase-Coupling
Negative symptoms
Working memory training
Lead sponsor: Tri-Service General Hospital
Sponsor class: OTHER
First posted: 2020-09-11
Enrollment: 36
Sex: ALL
Minimum age (years): 20
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this randomized double-blind trial, we investigated whether externally induced left-hemispheric frontoparietal theta synchronization by multi-electrode online theta (6Hz) transcranial alternating current stimulation (tACS) would enhance the influence of a working memory training on negative symptoms of schizophrenia.

Detailed description: Negative symptoms have a negative impact on the prognosis of schizophrenia, but effective treatment for this symptom dimension is still under investigation. Identifying a treatment target that has a close link to negative symptoms or highly impacts negative symptoms may help to develop an effective therapy to counteract negative symptoms of schizophrenia. Recent theoretical and empirical work linking negative symptoms and cognitive impairment in schizophrenia has identified a potential treatment target: cognitive deficits. Evidence has indicated that cognitive remediation (CR) has a positive effect on improving negative symptoms of schizophrenia, in particular behavioural negative symptoms.

Although it is still debated which active components of CR contribute to the improvements in negative symptoms. The framework proposed by Gold and colleagues may be a candidate to explain how CR improves negative symptoms (i.e., possible through improving working memory). Anhedonia (i.e., the diminished ability to experience pleasure and reduced reactivity to pleasurable stimuli) represents a challenging negative symptom in schizophrenia.The impairment in hedonic processing has been associated with reduced motivation to engage in potentially rewarding events. Working memory (WM) plays an important role in the formation, maintenance, and retrieval of affective and value representations, all of which are essential for anticipatory pleasure. Individuals represent events and forecast pleasure by using WM in order to recruit motivational resources. It has been suggested that there is a hedonic detector system within the WM model and that WM serves as a potential underlying cognitive mechanism for anticipatory pleasure and goal-related behaviours. Problems in WM may reduce the ability to retrieve and manipulate information to motivate and guide future behaviour, thereby contributing to diminished motivation and the pleasure experience. It is known that the recruitment of the prefrontal-striatal system (including dorsolateral prefrontal cortex, cingulate cortex, insula, and ventral striatum) implicates in hedonic processing. It is also known that the same brain regions can be viewed as core brain regions of the WM network because they are activated during WM load. The overlap in activation of the prefrontal-striatal system during hedonic processing and WM provides robust evidence supporting the relationship between hedonic capacity and WM. Evidence indicated a correlation between the activity in WM brain networks and the improvement in negative symptoms following antipsychotic treatment, suggesting a mediating effect of WM on negative symptoms improvement in the context of a pharmacological intervention. More recently, studies indicated that 20 sessions of WM training (dual n-back task training) showed neural transfer effect to enhance hedonic processing in individuals with high social anhedonia and ameliorate hedonic dysfunction in schizophrenia patients with prominent negative symptoms.

In addition to WM training, non-invasive brain stimulation (NIBS) is also a non-pharmacological method to improve brain neural plasticity. For example, repetitive transcranial magnetic stimulation (rTMS) can change the activity of cortical nerve temporarily or continuously and enhance neural plasticity. However, the ability of rTMS alone to improve cognitive function in schizophrenia is frequently limited to some extent, necessitating a combination with WM training to boost cognitive functions.

Transcranial alternating current stimulation (tACS), a safe NIBS technique that applies low-intensity alternating current, is also a potential therapeutic option in treating the cognitive impairment in schizophrenia. The stimulation frequency of tACS is usually set to coincide with the targeted brain endogenous rhythms. It would synchronize the neural oscillations in the stimulated cortical regions to the applied stimulation frequency. Different tACS current intensity (0.5 to 4 mA), stimulation frequency (0.1 to 80 Hz), electrode montages, phase difference across the stimulation site, with/without DC offset, and the states (e.g., at rest or concurrently under the tasks) during stimulation contribute to its different effects. If both the target electrode and the reference electrode are in the same phase of the cycle of the current at any given time, the phase difference will be 0 degree (i.e., in-phase). The phase difference will be 180 degrees (i.e., anti-phase) if the electrodes are in the opposite phase. In-phase and anti-phase tACS over brain regions elicits synchronization and desynchronization of neuronal activity across the brain regions, respectively.

The state-dependent tACS effects indicate that the effects of tACS are enhanced when the state of the targeted brain regions is active. Specifically, synchronization of frontoparietal regions at theta frequencies dominates during an executive task. tACS at the frequency close to the theta oscillation activated by an executive task would elicit more resonance and may, in turn, help to enhance executive function. tACS applied when an individual is concurrently engaged in a specific cognitive task is defined as online tACS. In healthy subjects, online theta (6Hz) in-phase tACS facilitated frontoparietal phase coupling (synchronization) resulting in improved WM performance, whereas online theta (6Hz) anti-phase tACS disrupted theta phase-coupling (desynchonization) resulting in impaired WM performance.

The prolonged after-effects of tACS may be related to a phenomenon called spike-timing-dependent plasticity (STDP), a process that modifies the connection strengths based on the relative timing of the input and output spikes (or action potentials) of a neuron. STDP means that synapse will be strengthened if input action potentials occur immediately before the output action potentials, and synapse will be made weaker if an input action potentials occur immediately after an output action potentials. The STDP process is known to explain in part long-term depression (LTD) and long-term potentiation (LTP) of nervous systems. To sum up, tACS at a frequency close to that of resonance frequency during tACS may intensify the synapses across the stimulated regions through the mechanism of STDP. Repetitive (multiple-session) tACS during specific time intervals may consolidate the neuroplasticity effects, and may, in turn, elicit a long-lasting effect for further clinical application in treating neuropsychiatric disorders. In schizophrenia patients, a few case reports indicated 1-5 sessions of online theta in-phase tACS over left frontoparietal regions improved the performance of WM and several other cognitive domains.

So far, there is no relevant research report exploring whether and how the joint intervention (i.e., online theta (6Hz) in-phase tACS over the left frontoparietal regions plus WM training) will have a combined effect on improving the performance of WM and other cognitive domains in schizophrenic patients. Neither is any research investigating whether online theta (6Hz) in-phase tACS over the left frontoparietal regions can potentiate the effects of WM training on improving negative symptoms of schizophrenia. To sum up, we hypothesize that the combination training mode of active online theta tACS plus WM training would have a greater ability to reduce negative symptoms of schizophrenia compared to the training mode of sham online theta tACS plus WM training. The study aims to test the efficacy of "active online theta tACS plus WM" versus "sham online theta tACS plus WM training" in improving negative symptoms, WM performance, and other cognitive domains performance of schizophrenia using a double-blinded, randomized sham-controlled trial design. In order to evaluate the efficacy of the interventions, we will use behavioral outcomes (e.g., negative symptoms assessment and neurocognitive assessment) and neurophysiological outcomes (e.g., EEG and heart rate variability).

Methods

Dual N back training

The study will use a dual n-back task for WM training. In this task, squares at 8 different locations will show up sequentially (stimulus length, 500 ms; inter-stimulus interval, 2,500 ms) on a computer screen every 3 seconds. Simultaneously with the presentation of the squares, one of eight consonants will show up sequentially through a speaker. Participants will have to judge whether the location of a square and the consonant they heard matches the one n-back before (the same n value for both visual and auditory targets). Each training session has 20 blocks consisting of 20 + n trials and takes around 25 min. Each block includes six auditory and six visual targets (four appearing in only one modality, and two appearing in both modalities simultaneously) whose locations are random. Participants will have to make responses manually by pressing the mouse left-click button for visual targets and the right-click button for auditory targets. No responses were required for non-targets. If a target is correctly detected, a green flash will be given, which constitutes a positive feedback. If a target is falsely detected, a blue flash will be given, which constitutes a negative feedback. The dual N back training is designed to continuously vary its difficulty by modifying the WM load (i.e., the level of n) and thereby track the participants' performance. Each training session begins at n = 1. Participants' performance will be analyzed after each block and the level of n for the next block will be adapted according to the following principle. The level of n increases by 1 in the next block if the mistakes per modality made by the participant are\<3. Conversely, n would decrease by 1 if the mistakes per modality made by the participant are\>5. In all other cases, the n is kept unchanged. Participants will come to the laboratory and take part in the WM training sessions twice daily for 5 weekdays (total 10 sessions), with each session lasting for approximately 25 minutes. The time interval between twice-daily sessions will be \>3 hours.

Online left-hemispheric frontoparietal theta (6Hz) in-phase tACS

θ tACS will be administered during the dual n-back task, starting at the beginning of each task and lasting for 20 min. In the active θ tACS condition, sinusoidal tACS will be delivered by two battery-operated devices connected with two 4 × 1 wire adaptors (Equalizer Box, NeuroConn, Ilmenau, Germany). The electrode montages used for θ tACS will be positioned at left frontoparietal locations. The stimulation electrodes of the 1st stimulator will be placed at the International 10-10 electrode position F1, F5, AF3, and FC3 (stimulation electrodes) and CPz (return electrode) to cover the left frontal cortex. For the 2nd stimulator, the stimulation electrodes will be placed at P1, P5, CP3, and PO3 (stimulation electrodes) and FCz (return electrode) to cover the left parietal cortex. A NeuroConn digital to analog converter (DAQ) will control the two stimulators and create an in-phase (synchronous) setup (0° relative phase difference between the output signals of the two tACS-stimulators).

Eligibility criteria: Inclusion Criteria:

1. Eligible participants aged 20-65 with DSM-V-defined schizophrenia or schizoaffective disorder.
2. Duration of illness \> 2 years.
3. Being clinically stable and on an adequate therapeutic dose of antipsychotics for at least 8 weeks prior to enrolment.
4. Agreement to participate in the study and provide the written informed consent.

Exclusion Criteria:

1. Having unstable medical conditions, current psychiatric comorbidity or active substance use disorder (in exception to caffeine and/or tobacco).
2. Having a history of seizures, meningitis or encephalitis.
3. Having contraindications for transcranial electrical stimulation or transcranial magnetic stimulation, e.g., pacemakers, metallic or magnetic pieces in the head/brain, ear implants and other implantible brain medical devices.
4. Having a history of intracranial neoplasms or surgery, or a history of severe head injuries or cerebrovascular diseases.
5. Pregnancy or breastfeeding at enrollment.
6. Skin lesions on scalp at the area of electrode application

Primary outcomes:
measure: The change over time in the negative symptoms subscale score of the Chinese version of the Positive and Negative Syndrome Scale (PANSS) (from baseline to the timepoints immediately after intervention, at one-week and one-month follow-ups).
timeFrame: Five weeks
Secondary outcomes:
measure: The change over time in the Chinese version of the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS) (from baseline to the timepoints immediately after intervention, at one-week and one-month follow-ups).
timeFrame: Five weeks
measure: The change over time in the score of the Chinese version of the Scale for the Assessment of Negative Symptoms (SANS) (from baseline to the timepoints immediately after intervention, at one-week and one-month follow-ups).
timeFrame: Five weeks
measure: The change over time in the score of the Chinese version of the Personal and Social Performance scale (PSP) (from baseline to the timepoints immediately after intervention, at one-week and one-month follow-ups).
timeFrame: Five weeks
measure: The change over time in the score of the self-reported version of the graphic personal and social performance scale (SRG-PSP) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The change over time in the score of the abbreviated version of the Scale to Assess Unawareness in Mental Disorder in schizophrenia (SUMD) (from baseline to the timepoints immediately after intervention, at one-week and one-month follow-ups).
timeFrame: Five weeks
measure: The change over time in the score of the Taiwanese version of the Beck Cognitive Insight Scale (BCIS) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The change over time in the score of the Taiwanese version of the Self-Appraisal of Illness Questionnaire (SAIQ) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The change over time in the negative symptoms subscale score of the Chinese version of the Schizophrenia Quality of Life Scale Revision Four (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Digit span (forward and backward) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Finger tapping test (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Continuous Performance (CPT, version 2.0) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Wisconsin Card Sorting Test (WCST) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Tower of London test (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Color Trails Test (CTT) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of Stroop Color Word Test (SCWT) (from baseline to the timepoints immediately after intervention and at one-week follow-up)
timeFrame: Two weeks
measure: The changes over time in the results of the dual 2-back task (from baseline to the timepoints immediately after intervention, at one-week and one-month follow-ups).
timeFrame: Five weeks
measure: The changes over time in indices of heart rate variability (HRV) measured at baseline, during the first session of tACS, after 10-session tACS, at 1-week and 1-month follow-ups.
timeFrame: Five weeks
measure: The changes over time in EEG absolute power and coherence in the frontoparietal electrode pairs in the alpha and theta range (from baseline to the timepoints after intervention, at one-week and one-month follow-ups)
timeFrame: Five weeks
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Tri-service general hospital
Study officials:
affiliation: Tri-Service General Hospital
name: Hsin-An Chang, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Alagapan S, Schmidt SL, Lefebvre J, Hadar E, Shin HW, Frӧhlich F. Modulation of Cortical Oscillations by Low-Frequency Direct Cortical Stimulation Is State-Dependent. PLoS Biol. 2016 Mar 29;14(3):e1002424. doi: 10.1371/journal.pbio.1002424. eCollection 2016 Mar.
citation: Battleday RM, Muller T, Clayton MS, Cohen Kadosh R. Mapping the mechanisms of transcranial alternating current stimulation: a pathway from network effects to cognition. Front Psychiatry. 2014 Nov 20;5:162. doi: 10.3389/fpsyt.2014.00162. eCollection 2014. No abstract available.
citation: Cella M, Preti A, Edwards C, Dow T, Wykes T. Cognitive remediation for negative symptoms of schizophrenia: A network meta-analysis. Clin Psychol Rev. 2017 Mar;52:43-51. doi: 10.1016/j.cpr.2016.11.009. Epub 2016 Nov 28.
citation: Farreny A, Aguado J, Ochoa S, Haro JM, Usall J. The role of negative symptoms in the context of cognitive remediation for schizophrenia. Schizophr Res. 2013 Oct;150(1):58-63. doi: 10.1016/j.schres.2013.08.008. Epub 2013 Aug 29.
citation: Fusar-Poli P, Papanastasiou E, Stahl D, Rocchetti M, Carpenter W, Shergill S, McGuire P. Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials. Schizophr Bull. 2015 Jul;41(4):892-9. doi: 10.1093/schbul/sbu170. Epub 2014 Dec 20. Erratum In: Schizophr Bull. 2022 May 7;48(3):721. doi: 10.1093/schbul/sbz071.
citation: Gold JM, Barch DM, Carter CS, Dakin S, Luck SJ, MacDonald AW 3rd, Ragland JD, Ranganath C, Kovacs I, Silverstein SM, Strauss M. Clinical, functional, and intertask correlations of measures developed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia Consortium. Schizophr Bull. 2012 Jan;38(1):144-52. doi: 10.1093/schbul/sbr142. Epub 2011 Nov 17.
citation: Gold JM, Waltz JA, Prentice KJ, Morris SE, Heerey EA. Reward processing in schizophrenia: a deficit in the representation of value. Schizophr Bull. 2008 Sep;34(5):835-47. doi: 10.1093/schbul/sbn068. Epub 2008 Jun 30.
citation: Jaeggi SM, Buschkuehl M, Jonides J, Perrig WJ. Improving fluid intelligence with training on working memory. Proc Natl Acad Sci U S A. 2008 May 13;105(19):6829-33. doi: 10.1073/pnas.0801268105. Epub 2008 Apr 28.
citation: Klimesch W. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Brain Res Brain Res Rev. 1999 Apr;29(2-3):169-95. doi: 10.1016/s0165-0173(98)00056-3.
citation: Kringelbach ML, Berridge KC. Towards a functional neuroanatomy of pleasure and happiness. Trends Cogn Sci. 2009 Nov;13(11):479-87. doi: 10.1016/j.tics.2009.08.006. Epub 2009 Sep 24.
citation: Lett TA, Voineskos AN, Kennedy JL, Levine B, Daskalakis ZJ. Treating working memory deficits in schizophrenia: a review of the neurobiology. Biol Psychiatry. 2014 Mar 1;75(5):361-70. doi: 10.1016/j.biopsych.2013.07.026. Epub 2013 Sep 5.
citation: Li X, Chu MY, Lv QY, Hu HX, Li Z, Yi ZH, Wang JH, Zhang JY, Lui SSY, Cheung EFC, Shum DHK, Chan RCK. The remediation effects of working memory training in schizophrenia patients with prominent negative symptoms. Cogn Neuropsychiatry. 2019 Nov;24(6):434-453. doi: 10.1080/13546805.2019.1674644. Epub 2019 Oct 4.
citation: Li X, Li Z, Li K, Zeng YW, Shi HS, Xie WL, Yang ZY, Lui SS, Cheung EF, Leung AW, Chan RC. The neural transfer effect of working memory training to enhance hedonic processing in individuals with social anhedonia. Sci Rep. 2016 Oct 18;6:35481. doi: 10.1038/srep35481.
citation: Li X, Xiao YH, Zou LQ, Li HH, Yang ZY, Shi HS, Lui SS, Cheung EF, Chan RC. The effects of working memory training on enhancing hedonic processing to affective rewards in individuals with high social anhedonia. Psychiatry Res. 2016 Nov 30;245:482-490. doi: 10.1016/j.psychres.2016.09.006. Epub 2016 Sep 8.
citation: Nejad AB, Madsen KH, Ebdrup BH, Siebner HR, Rasmussen H, Aggernaes B, Glenthoj BY, Baare WF. Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients. Int J Neuropsychopharmacol. 2013 Jul;16(6):1195-204. doi: 10.1017/S1461145712001253. Epub 2012 Nov 20.
citation: Polania R, Nitsche MA, Korman C, Batsikadze G, Paulus W. The importance of timing in segregated theta phase-coupling for cognitive performance. Curr Biol. 2012 Jul 24;22(14):1314-8. doi: 10.1016/j.cub.2012.05.021. Epub 2012 Jun 7.
citation: Rottschy C, Langner R, Dogan I, Reetz K, Laird AR, Schulz JB, Fox PT, Eickhoff SB. Modelling neural correlates of working memory: a coordinate-based meta-analysis. Neuroimage. 2012 Mar;60(1):830-46. doi: 10.1016/j.neuroimage.2011.11.050. Epub 2011 Dec 1.
citation: Sreeraj VS, Shanbhag V, Nawani H, Shivakumar V, Damodharan D, Bose A, Narayanaswamy JC, Venkatasubramanian G. Feasibility of Online Neuromodulation Using Transcranial Alternating Current Stimulation in Schizophrenia. Indian J Psychol Med. 2017 Jan-Feb;39(1):92-95. doi: 10.4103/0253-7176.198937.
citation: Sreeraj VS, Shivakumar V, Sowmya S, Bose A, Nawani H, Narayanaswamy JC, Venkatasubramanian G. Online Theta Frequency Transcranial Alternating Current Stimulation for Cognitive Remediation in Schizophrenia: A Case Report and Review of Literature. J ECT. 2019 Jun;35(2):139-143. doi: 10.1097/YCT.0000000000000523.
citation: Strauss GP. Translating basic emotion research into novel psychosocial interventions for anhedonia. Schizophr Bull. 2013 Jul;39(4):737-9. doi: 10.1093/schbul/sbt082. Epub 2013 May 24. No abstract available.
citation: Vinograd M, Craske MG. Using Neuroscience to Augment Behavioral Interventions for Depression. Harv Rev Psychiatry. 2020 Jan/Feb;28(1):14-25. doi: 10.1097/HRP.0000000000000241.
citation: Vossen A, Gross J, Thut G. Alpha Power Increase After Transcranial Alternating Current Stimulation at Alpha Frequency (alpha-tACS) Reflects Plastic Changes Rather Than Entrainment. Brain Stimul. 2015 May-Jun;8(3):499-508. doi: 10.1016/j.brs.2014.12.004. Epub 2014 Dec 20.
citation: Zaehle T, Rach S, Herrmann CS. Transcranial alternating current stimulation enhances individual alpha activity in human EEG. PLoS One. 2010 Nov 1;5(11):e13766. doi: 10.1371/journal.pone.0013766.