An Open-Label, Single-Arm Trial of Transcranial and Intranasal Photobiomodulation in Patients with Schizophrenia: A Study Protocol

Introduction

Schizophrenia is a chronic psychiatric illness with a global prevalence of approximately 1%. If not appropriately treated, affected individuals often experience poor functional outcomes.^1,2 In addition to positive and negative symptom dimensions, schizophrenia is associated with impairments across multiple domains of cognitive functioning, including verbal memory, executive function, and working memory.^3,4 Although antipsychotic therapy is central to the management of schizophrenia, cognitive impairment associated with schizophrenia (CIS) frequently persists.^1,2 This is clinically important, as cognitive functioning is a key determinant of functional recovery, including return to work or education, underscoring the need for therapeutic strategies targeting CIS.^5–10

Efforts to address CIS have included pharmacological augmentation¹¹ and cognitive remediation.¹² However, their efficacy has yet to be established,^13,14 highlighting the need for novel treatment approaches. In this context, non-invasive brain stimulation (NIBS), a low-risk neuromodulation technique that alters neural activity through physical stimulation, has attracted considerable attention.¹⁵

Among NIBS approaches, techniques based on electromagnetic principles, such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS), have attracted significant interest as potential interventions for psychiatric and neurological conditions.^16,17 Previous studies, including work from our group, have suggested that tDCS may contribute to improvements in cognitive performance and functional abilities in individuals with schizophrenia.¹⁸ Moreover, changes in cerebral hemodynamics assessed using near-infrared spectroscopy (NIRS) have been shown to relate to treatment-associated symptom changes, highlighting the potential relevance of neurophysiological markers in understanding and monitoring therapeutic responses.¹⁹

In addition, tDCS has been reported to improve emotional recognition, a key component of social cognition, possibly through modulation of neural activity in the superior temporal sulcus.²⁰ Nevertheless, some patients still express reluctance toward tDCS due to the discomfort that can arise from scalp-applied electrical currents (eg., tingling sensations), underscoring the need for even less invasive and more tolerable approaches.^21,22

Photobiomodulation (PBM) is a non-invasive therapeutic approach that utilizes low-intensity visible or near-infrared light to modulate biological processes.^23,24 Rather than inducing thermal effects, PBM is thought to influence cellular metabolism and tissue-level physiology. Advances in light-delivery technologies, including the development of cost-effective light-emitting diodes (LEDs), have facilitated the broader application of PBM in both experimental and clinical contexts.²⁵

From a mechanistic perspective, the biological effects of PBM are considered to depend on wavelength and irradiation parameters. Red-to-near-infrared light is characterized by relatively high tissue penetration, whereas shorter wavelengths may induce different biological responses depending on irradiation intensity.^14,26,27 At low irradiation levels, PBM is hypothesized to interact with intracellular photoacceptors, including mitochondrial components, leading to downstream changes in cellular metabolism.²⁸ In particular, modulation of mitochondrial function has been proposed to influence adenosine triphosphate production and redox signaling pathways.²⁹ These processes may also involve nitric oxide–related signaling, which has been implicated in neurovascular regulation.³⁰ Consistent with this framework, transcranial PBM has been associated with alterations in cerebral perfusion and metabolic activity.^27,29

Recent advances in PBM have facilitated the optimization of stimulation parameters, including the temporal pattern of light delivery. In particular, the shift from continuous to pulsed stimulation, a key development in pulse mode, has been shown to enhance tissue energy absorption and may modulate neural oscillations, such as alpha (10 Hz) and gamma (40 Hz) rhythms.³¹ In addition, the co-administration of intranasal PBM may provide a pathway for influencing deeper cortical regions, including the ventromedial prefrontal and orbitofrontal cortices.^32,33 Specifically, intranasal stimulation may be advantageous for influencing subcortical regions, including limbic and striatal structures such as the amygdala, hippocampus, thalamus, and nucleus accumbens, which are known to play key roles in schizophrenia-related neural dysfunction.³⁴ Together with the miniaturization and greater cost-effectiveness of LED devices, these advances have heightened expectations for PBM in the treatment of neurological and psychiatric disorders, particularly with respect to cognitive enhancement. In line with this, devices developed by Vielight have been registered as “General Wellness Devices,” a category defined by the U.S. Food and Drug Administration as low-risk devices intended to promote a healthy lifestyle rather than as a treatment for specific medical conditions.^35,36 It is therefore essential to evaluate the safety and efficacy of these devices,^37,38 that may produce clinical benefits in patients with schizophrenia.

Potential mechanisms through which transcranial PBM may contribute to improvements in CIS can be inferred by drawing on evidence from studies examining cognitive outcomes in dementia. In a case series, Saltmarche et al evaluated five patients with mild to moderately severe dementia using the Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).³³ After 12 weeks of pulsed near-infrared treatment, MMSE scores improved by a mean of 2.60 points (17.4 to 20.0; p < 0.003), while ADAS-Cog scores improved by a mean of 6.74 points in a favorable direction (35.47 to 28.73; p < 0.023).³³ In a sham-controlled study, Chan et al examined 18 older adults with mild cognitive impairment using a visual memory span task and reported that a single session of photobiomodulation was associated with improved visual memory performance in the active-treatment group, whereas no such improvement was observed in the sham group.³⁷

These clinical observations are supported by preclinical findings indicating that 40-Hz PBM can reduce amyloid-β plaque burden in murine models of Alzheimer’s disease, potentially through mechanisms involving enhanced amyloid clearance and modulation of neuroinflammatory processes.³⁹ Given the well-established association between amyloid pathology and cognitive decline, this evidence collectively provides a biological basis for investigating PBM as a candidate intervention for cognitive impairment in humans.³⁹

To date, only one randomized controlled trial has examined the effects of PBM in individuals with schizophrenia. In that study, Kheradmand et al (2022) administered PBM at wavelengths of 630 and 810 nm to 32 individuals with chronic schizophrenia three times per week for two weeks.⁴⁰ Cognitive function was assessed using the MMSE, and no significant improvement in cognitive performance was observed compared with sham stimulation.⁴⁰ Several methodological factors may partly explain the absence of cognitive benefits in that study. First, the intervention period was relatively short (two weeks), which may have been insufficient to induce measurable neurocognitive changes. Second, cognition was assessed using the MMSE, a screening instrument primarily designed for dementia and not specifically sensitive to the executive and attentional deficits that characterize cognitive impairment in schizophrenia. These limitations highlight the need for further investigation using optimized stimulation parameters and more appropriate cognitive assessment tools. Based on these considerations, the present study primarily aims to evaluate the safety and tolerability of PBM and to explore its potential effects in individuals with CIS.

Methods and Analysis

Trial Design

The study is designed as an open-label, single-arm clinical investigation conducted at a single academic center. Individuals with CIS will participate in a 12-week intervention period during which active PBM will be administered on site. PBM sessions will be conducted three times per week, with each session lasting 20 minutes. The intervention consists of non-visible near-infrared light delivered through six applicators: one intranasal probe, one frontal scalp applicator, one vertex scalp applicator, two temporal scalp applicators (left and right), and one occipitoparietal applicator positioned over the occipital scalp. Given the single-arm open-label design of this exploratory study, placebo effects, Hawthorne effects, and other non-specific influences cannot be fully controlled. To minimize variability, assessments will be conducted using predefined procedures and standardized outcome measures at fixed evaluation time points.

This protocol was developed in accordance with the SPIRIT 2025 statement, and the SPIRIT checklist is provided as Supplementary Material.

Participants

We will recruit patients at the National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan. Potential participants will be referred by their treating psychiatrists or neurologists and receive a brochure with brief information on the trial after their appointments. Participants who express interest will provide informed consent to the principal investigator or other investigators using an Informed Consent Form. Only those who fully understand the purpose and procedures of the study and provide written informed consent will be enrolled. The inclusion criteria are as follows: 1) having a primary diagnosis of schizophrenia according to DSM-5; 2) being aged 18 years or older but younger than 70 years at the time of the first stimulation (the upper limit was set in consideration of treatment safety); 3) being able to understand the study information and voluntarily provide consent; 4) having a score ≤ 0.5 standard deviations below the mean on either the WAIS Digit Symbol Coding subtest or the Rey Auditory Verbal Learning Test (15-word version), as the study targets individuals with below-average cognitive functioning. The “or” criterion was adopted to capture domain-specific cognitive deficits while maintaining recruitment feasibility, given the heterogeneous nature of cognitive impairment in schizophrenia. A less stringent threshold (0.5 SD below the normative mean) will be used to identify mild or selective impairments in key domains such as processing speed and verbal learning. This approach is consistent with psychosis-spectrum research using similar thresholds (eg., Carrión et al, 2025).⁴¹ Therefore, this criterion was considered appropriate for this exploratory feasibility-oriented pilot study. The following groups will be excluded from the study: 1) patients with severe organic brain lesions, a history of head trauma involving loss of consciousness longer than 10 minutes, or comorbid or previous epilepsy; 2) those with comorbid alcohol or substance use disorder (excluding caffeine and nicotine) within 12 months of the baseline evaluation; 3) patients diagnosed with intellectual disability; 4) those for whom electroconvulsive therapy is clinically contraindicated (eg., due to a history of significant head trauma); 5) patients who have received cognitive remediation therapy within the past month; and 6) individuals deemed unsuitable for participation by the investigators. Because PBM uses low-level light stimulation and is generally considered a low-risk intervention, patients receiving other neuromodulation therapies (eg., rTMS or tDCS) will not be explicitly excluded from participation. In the Japanese clinical context, these neuromodulation therapies are not established as standard treatments for schizophrenia. Although not explicitly listed as exclusion criteria in the protocol, pregnant or breastfeeding women will not be enrolled due to safety considerations.

Intervention

The intervention will be administered using the Vielight Neuro Gamma 4 system (Vielight Inc., Toronto, Ontario, Canada), a PBM device that emits near-infrared light through six LED applicators. These applicators are positioned to irradiate the frontal, temporal (left and right), vertex, occipitoparietal, and intranasal regions (Figures 1 and 2).

Figure 1 Frontal view of the transcranial photobiomodulation setup. The device consists of a nasal applicator and a headset with four LED modules positioned over the default mode network hubs. The sensor plate includes four measurement channels positioned over the frontal cortex to monitor hemodynamic changes associated with cognitive task performance.

Figure 2 Partial view of the transcranial photobiomodulation setup. The figure illustrates the positioning of the LED modules and the nasal applicator targeting the default mode network hubs.

The therapeutic effects of PBM depend on several key parameters, including wavelength, irradiance, fluence, and spot size. Wavelength (nm) determines the depth of tissue penetration and the type of biological response. Irradiance (mW/cm²) represents the power delivered per unit area and defines the intensity of stimulation received by cells. Fluence (J/cm²), calculated as irradiance multiplied by exposure time, indicates the total energy delivered to the tissue and is a major determinant of biological outcomes. Spot size (cm²) refers to the illuminated area and influences the distribution of energy density, affecting both the precision and reproducibility of PBM treatments.^42–44

Each treatment session will involve intermittent photonic stimulation at a wavelength of 810 nm, delivered at 40 Hz with a duty cycle of 50% for a total duration of 20 minutes. The administered energy density will be 60 J/cm² over the frontal area, 15 J/cm² in total over the occipitoparietal region, and 15 J/cm² via the intranasal applicator. The device delivers site-specific output power densities of 100 mW/cm² over the frontal area and 25 mW/cm² over the occipitoparietal region and via the intranasal applicator. Given a total session duration of 1200 seconds, these parameters yield the intended energy densities after accounting for the duty cycle.

Although substantial attenuation of light occurs within biological tissues, previous studies suggest that PBM may exert cellular effects even when relatively low levels of energy reach the tissue surface.⁴⁵ On this basis, the applied dosage may have the potential to influence neural activity in deeper brain regions. For safety and consistency, all devices are fitted with a visual indicator and are programmed to automatically terminate light emission after 20 minutes.

The PBM parameters used in this study were selected based on previous clinical and experimental studies using the Vielight Neuro device.³⁵ The wavelength of 810 nm has been widely used in PBM research because of its favorable tissue penetration and its interaction with mitochondrial chromophores, particularly cytochrome c oxidase.²⁸ The pulsed 40 Hz frequency was selected based on evidence suggesting that gamma-frequency stimulation may enhance neural synchronization and cognitive processing.³¹ Although Kheradmand et al (2022) reported negative findings using PBM in schizophrenia, differences in stimulation parameters, treatment duration, and study design may lead to differing outcomes.⁴⁰ Therefore, the present study adopts parameters that have been commonly used in PBM neuromodulation research to further explore their potential therapeutic effects.

Procedure

Eligible participants will be enrolled only after a detailed explanation of the study objectives and the provision of written informed consent. Assessments will be performed at multiple time points depending on the outcome measure, including baseline, during the intervention period, immediately after the completion of the intervention (3 months), and at 6 months (Table 1). Interventions will be conducted by clinicians and experienced medical staff. Although both PBM and NIRS utilize near-infrared light, NIRS measurements will be conducted separately from PBM stimulation sessions to avoid potential optical interference between the stimulation device and the hemodynamic signal acquisition. Safety and tolerability will be assessed more frequently, including at baseline, 1 week after treatment initiation, immediately before and after each PBM session, and during scheduled follow-up visits. Cognitive function will be evaluated using the MATRICS Consensus Cognitive Battery (MCCB), which has established reliability and validity in schizophrenia research. Neurophysiological measures including mismatch negativity (MMN) and NIRS will be obtained using standardized experimental protocols. Data will be recorded using predefined case report forms and reviewed to ensure data quality. All assessments will be conducted by trained investigators according to standardized procedures. Participants will continue their usual pharmacological treatment under the supervision of their treating physicians, and no protocol-driven restrictions on medication changes will be imposed. Study participation will be discontinued under any of the following conditions: (1) withdrawal of informed consent; (2) participant request to discontinue participation for any reason (eg., relocation or transfer to another institution); (3) occurrence of a disease or medical condition, including serious illness or adverse events; (4) insufficient therapeutic effect or worsening of the primary condition; (5) failure to attend scheduled visits or inability to establish contact; (6) determination by the principal investigator or sub-investigators that continued participation would impose an excessive physical or psychological burden; (7) identification of a major protocol deviation (eg., post hoc ineligibility); or (8) any other reason deemed appropriate by the principal investigator. Participation in this study will involve clinical and psychological assessments, which may impose a burden on participants. To mitigate this burden, participants will receive QUO cards (a prepaid gift card commonly used in Japan) as compensation according to a predefined schedule.

Table 1 Schedule of the Study

Primary Outcome

Safety and Tolerability

The primary endpoint of this study is safety and tolerability, evaluated based on the incidence and frequency of adverse events recorded at baseline, 1 week, 3 months, and 6 months. No major device-related risks have been reported for the Vielight PBM system. Similarly, previous literature has not identified clear safety risks associated with PBM.^46,47 A few reports have described isolated cases of severe headache⁴⁶ and increased diastolic blood pressure;⁴⁷ however, a direct causal relationship with the device has not been established. Given the mechanism of action and relatively low energy output of the device, it remains important to evaluate even minor physical or psychological changes from a safety perspective. Adverse events will be classified according to a previous systematic review.²¹ In addition, since Vielight has stated that “some users may experience mild and temporary side effects, such as headaches, dizziness, or slight discomfort at the application site”,³⁵ we will also include items related to discomfort at the nasal and cranial application sites among the potential side effects examined. Safety assessments will be conducted using a predefined symptom checklist administered before and after each PBM session (Figure 3). If any adverse event is identified during this screening, detailed information including onset, severity, outcome, and causality will be recorded using a standardized adverse event reporting form (Figure 4). All adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA)⁴⁸ and summarized by severity.

Figure 3 Safety checklist.

Figure 4 Adverse event reporting form.

All reported adverse events will be reviewed and managed by the principal investigator in accordance with the institutional procedures governing the management of adverse events and device-related malfunctions at the NCNP.⁴⁸ If a serious adverse event is identified, continuation of study participation will be re-evaluated, and discontinuation will be considered based on clinical judgment.

Secondary Outcomes

Cognitive Assessment

The MATRICS Cognitive Consensus Battery (MCCB)

The MCCB is a comprehensive battery for assessing cognitive functioning in patients with schizophrenia.^49,50 It consists of neuropsychological subtests covering seven cognitive domains (speed of processing, working memory, attention/vigilance, reasoning and problem solving, verbal learning, visual learning, social cognition). The raw scores are transformed into T-scores, and then the domain scores (attention/vigilance, verbal learning, visual learning, reasoning and problem solving, and social cognition), and the composite scores (working memory, speed of processing, and MCCB Total) are produced according to the manual.⁵⁰ The T-score for each task corresponds to the domain score except for speed of processing (Trail Making Test, BACS Symbol Coding, and Fluency) and working memory (Letter Number Sequencing and Wechsler Memory Scale Spatial Span). For these domains, the scores are calculated by summing the T-scores of the tests included in the domains. The total composite score is the sum of the seven domain scores. We have previously presented a method for converting raw scores to T-scores for the Japanese version of this measure.⁵⁰

Social Cognition Rating Scale (SCoRS)

The SCoRS is one of the interview-based measures of cognition. It consists of 20 questions that measure attention, memory, reasoning and problem solving, working memory, language production, and motor skills, which are related to day-to-day functioning.⁵¹

Specific Levels of Functioning Scale (SLOF)

Everyday functional capacity will be evaluated using the Specific Levels of Functioning Scale (SLOF), an informant-based assessment developed to capture real-world functioning in individuals with psychiatric conditions, including schizophrenia. The instrument comprises 43 items spanning multiple domains of functioning, such as physical abilities, self-care, interpersonal behavior, social appropriateness, community engagement, and vocational skills. Item responses are recorded on a 5-point Likert scale, with higher scores reflecting better functional performance.^52–54

Previous studies have demonstrated that the SLOF provides reliable and valid indices of functional outcome in schizophrenia.^52–54 In accordance with recent literature, the present study will focus on three core SLOF domains: Interpersonal Functioning, Everyday Activities, and Vocational Functioning. These domains encompass behaviors related to social interaction and communication, independent engagement in daily activities, and work-related skills and task performance. Summary scores derived from these domains will be used for analysis, consistent with prior reports.^9,52–54

Satisfaction with Life Scale (SWLS)

The SWLS is a widely used 5-item self-report tool measuring global life satisfaction—a cognitive component of subjective well-being.⁵⁵ This item, hereafter called the Life Satisfaction Scale (LSS), is rated 1–7 (“very dissatisfied” to “very satisfied”). Good life satisfaction will be defined as an LSS score ⩾5 (“slightly satisfied” or better).⁵⁵

Clinical Assessments

Scale for the Assessment of Positive Symptoms (SAPS)

Positive symptoms will be evaluated using the SAPS, originally developed by Andreasen. This instrument is used to characterize the severity and distribution of positive symptomatology in schizophrenia. The scale is composed of four symptom domains—hallucinations, delusions, bizarre behavior, and positive formal thought disorder—and includes a total of 34 items.⁵⁶

Scale for the Assessment of Negative Symptoms (SANS)

Negative symptoms will be assessed with the Scale for the Assessment of Negative Symptoms (SANS), also developed by Andreasen. The SANS captures multiple dimensions of negative symptomatology in schizophrenia and comprises five domains: affective flattening, alogia, apathy, anhedonia, and attentional impairment. The instrument consists of 25 items in total.⁵⁷

Montgomery-Asberg Depression Rating Scale (MADRS)

Depressive symptom severity will be quantified using the Montgomery–Asberg Depression Rating Scale (MADRS). This clinician-rated scale includes 10 items, each scored on a 7-point scale ranging from 0 to 6, yielding a total score between 0 and 60. Higher total scores indicate greater depressive severity.⁵⁸

Neurophysiological Assessments

Mismatch Negativity (MMN)

MMN will be assessed using an auditory oddball task during electroencephalographic (EEG) recording. In this paradigm, two types of auditory stimuli are presented: frequent standard tones and infrequent deviant tones. The analysis focuses on the brain responses elicited by the deviant stimuli. MMN is an event-related potential characterized by a negative deflection occurring approximately 100–250 ms after the presentation of a deviant auditory stimulus.^59,60 MMN reflects pre-attentive auditory processing and is considered an index of the brain’s automatic detection of violations in auditory regularities. Previous studies have consistently reported that MMN amplitude is reduced in individuals with schizophrenia, indicating impairments in early auditory information processing. Because MMN represents the neural response to unexpected auditory events, it has also been interpreted as a neural correlate of prediction error processing within hierarchical predictive coding frameworks. In the present study, both MMN amplitude and peak latency will be quantified for further analysis.

Near-Infrared Spectroscopy (NIRS)

We will employ the Brain Activity Monitor (Hb131S; Astem, Japan), a wearable NIRS device equipped with an ultra-thin sensor plate installed inside a sun visor. The device measures regional blood volume changes in the frontal lobe using four fixed channels, with sampling rates adjustable between 0.1 and 1.0 seconds per sample. The measured parameters will include regional oxygen saturation (rSO₂), oxyhemoglobin (oxy-Hb), deoxyhemoglobin (deoxy-Hb), and total hemoglobin (total-Hb). To evaluate frontal lobe activation under cognitive load, participants will perform a calculation task⁶¹ and a verbal fluency task.^19,62 For the calculation task, NIRS signals will be analyzed using the z-score transformation method described by Tsunashima et al, followed by the estimation of the maximum gradient (slope) of oxy-Hb to quantify rapid changes in hemodynamic response under an increasing workload.⁶¹ The calculation task will involve mental arithmetic problems with three levels of varying difficulty presented in a block design. The verbal fluency task will consist of a 30-s baseline period during which participants will repeatedly vocalize Japanese vowels, followed by a 60-s word-generation period in which participants will produce as many words as possible beginning with presented initial letters, and a 70-s post-task baseline period.^19,62 For the verbal fluency task, two additional indices will be computed; the center of gravity of the oxy-Hb waveform, reflecting the temporal distribution of activation, and the integral value (AUC), representing the total hemodynamic response throughout the task.^19,62

Sample Size Calculation

A sample size calculation was performed to determine the number of participants necessary to detect changes in the MCCB total score, from baseline to 3 months. As no prior studies have assessed the efficacy of PBM in patients with schizophrenia using the MCCB score, we referred to Fleischhacker et al (2021),⁶³ an early-phase trial with a comparable patient population and the same outcome measure, to estimate the standard deviation. Specifically, based on the reported standard error of the mean change in MCCB scores at 12 weeks, the standard deviation of the MCCB score change was estimated to be 6.0 points.

In addition, referring to Narita et al’s study (2020),⁶⁴ which reported an effect size of 0.49 for tDCS on cognitive function in schizophrenia, we assumed a mean MCCB score change of 3 points. A one-sample t-test for the score change, with a two-sided significance level of 10%, an effect size of 0.5, and 70% power, indicated that 20 participants were required. Given the exploratory nature of this pilot study and the limited prior evidence regarding the effects of PBM on cognitive function in schizophrenia, a two-sided significance level of α = 0.10 and statistical power of 70% were adopted to facilitate detection of potential signals and to estimate effect sizes for future confirmatory trials. Accordingly, the primary efficacy outcome (ie., MCCB) will be presented with a 90% confidence interval consistent with the predefined significance level, as well as conventional 95% confidence interval. For secondary outcomes, 95% confidence intervals will be reported to enhance interpretability and enable comparison with conventional reporting standards. Allowing for a dropout rate of 20%, the target sample size was set at 25 participants.

Data Management

To evaluate the intervention, assessments will be conducted by clinicians and experienced psychologists at baseline and during follow-up visits at 3 and 6 months (Table 1 and Figure 5). Participants will complete scheduled questionnaires and report any adverse events between visits.

Figure 5 Study flowchart.

All data, except for the informed consent documents, will be anonymized, entered into a secure database and verified by independent data managers. Data monitors will oversee trial conduct and review study progress. Participants may withdraw consent or discontinue participation at any time. Nevertheless, data will be collected as comprehensively as possible unless consent is withdrawn or a serious protocol deviation occurs.

If a serious medical condition occurs and a causal relationship with PBM cannot be ruled out, the case will be referred to the Effectiveness and Safety Evaluation Committee for further review and assessment. Any necessary protocol amendments and related decisions will be reported to the clinical research review board and the Ministry of Health, Labour and Welfare, and the updated information will be reflected in the Japan Registry of Clinical Trials. The findings will be disseminated through publication in a peer-reviewed journal.

Data Security and Quality Control

Data entry, coding, security, and storage will be managed by the Data Management Office of the Department of Clinical Research and Education at NCNP. The data manager will be responsible for database design and data management procedures. Data recorded into the case report forms will be checked and verified to ensure accuracy and completeness. Central monitoring procedures will also be conducted to support data quality control. Personal information will be handled in accordance with institutional regulations to maintain confidentiality and ensure secure data storage throughout the study.

Statistical Analysis

The full analysis set (FAS) will include all participants who receive at least one PBM session and undergo at least one post-baseline efficacy assessment. Participants with major protocol violations will be reviewed prior to database lock. The safety analysis set (SAS) will include all participants who receive at least one PBM session and have at least one safety observation recorded.

Longitudinal efficacy analyses will be performed using a mixed model for repeated measures (MMRM), which allows the use of all available observations without imputation under the assumption that data are missing at random. For analyses requiring complete data on specific variables, participants with missing information will be excluded from the corresponding analysis.

Given the exploratory nature of this pilot study and the limited prior evidence regarding PBM effects on cognitive function in schizophrenia, a two-sided significance level of α = 0.10 and statistical power of 70% were adopted to estimate potential effect sizes for future confirmatory trials. Accordingly, the main efficacy outcome will be presented with a 90% confidence interval corresponding to the predefined significance level. For secondary outcomes, 95% confidence intervals will be reported to facilitate interpretation and comparison with conventional reporting standards.

For the primary exploratory efficacy outcome, the change in the MCCB total score (T-score) from baseline to the 3-month assessment will be evaluated. For secondary efficacy outcomes, excluding MMN and NIRS, which are not assessed at 6 months, changes from baseline to 3 and 6 months will be analyzed using an MMRM with time (3 or 6 months) as an explanatory variable.

Changes in MMN and NIRS will be analyzed separately using t-distribution–based estimates rather than MMRM, because these measures are not assessed longitudinally across all time points.

Safety outcomes will be summarized descriptively. Adverse events will be coded using the latest version of MedDRA and summarized by severity.

As supplementary analyses, changes in the MCCB total score will be examined using MMRM models excluding participants with insufficient PBM exposure (eg., fewer than 29 sessions). Additional models including the baseline MCCB score, NIRS, MMN, age, and sex as baseline covariates will also be explored.

Because prior PBM studies assessing cognitive outcomes in schizophrenia using the MCCB are lacking, the parameters used in the sample size calculation were informed by related intervention studies.⁶³ The expected effect size was referenced from a neuromodulation study using tDCS targeting cognitive function in schizophrenia, while the standard deviation was estimated from a schizophrenia intervention study reporting MCCB outcomes.⁶⁴

Discussion

Cognitive impairment in schizophrenia plays a central role in functional outcomes, including academic and occupational performance, and remains a major barrier to social reintegration. Against this background, the primary aim of the present study is to assess the safety and tolerability of PBM, while secondary analyses will explore its potential effects for cognitive functioning in individuals with schizophrenia.

To date, only one small study of PBM has targeted patients with schizophrenia, but without reporting safety and tolerability outcomes. Furthermore, the combined application of transcranial and intranasal PBM has not yet been investigated. Accordingly, the present study aims to generate foundational data on the safety and tolerability of combined transcranial and intranasal PBM in individuals with schizophrenia. Specifically, data on adverse events, treatment adherence, and protocol feasibility will provide valuable insights for the design of subsequent Phase 2 or Phase 3 clinical trials, although any observed changes should be interpreted as hypothesis-generating.

The proposed study has several strengths. First, it represents an initial clinical evaluation of PBM safety in individuals with schizophrenia and may provide foundational evidence to support the future establishment of clinical treatment guidelines. In addition, the study focuses on a critical and unresolved clinical challenge, ie., CIS, which is necessary to address to facilitate social reintegration for patients. Thus, this research may provide evidence on a novel therapeutic option for this unmet clinical need. The PBM device used in this study falls within the category of General Wellness Devices as defined by the U.S. Food and Drug Administration, suggesting a favorable safety profile and minimal invasiveness.^35,36 Photosensitivity reactions have been reported with certain antipsychotic medications, particularly older agents such as phenothiazines, although such effects are relatively uncommon with newer atypical antipsychotics. In the present study, PBM utilizes low-level near-infrared light (810 nm), which penetrates tissue with minimal photochemical effects on the skin compared to shorter wavelengths. Accordingly, the risk of clinically significant photosensitivity is presumed to be low. However, the interaction between PBM and photosensitizing medications has not been fully elucidated. Therefore, while a substantial risk is not anticipated, it cannot be completely excluded. Participants will be carefully monitored for any unexpected adverse events, including potential photosensitivity reactions. This approach is consistent with the primary aim of this study to evaluate safety and feasibility. In addition to transcranial application, the device allows intranasal stimulation, which may facilitate modulation of subcortical regions that are typically less accessible using conventional non-invasive brain stimulation approaches such as tDCS.

Several potential limitations should be considered regarding the current research protocol. First, the study is conducted at a single center with a relatively small sample size, which may limit the generalizability of the findings. Second, the open-label, single-arm design precludes definitive conclusions regarding clinical efficacy, as observed effects may reflect placebo effects, Hawthorne effects, or other non-specific influences. Accordingly, larger, multicenter, controlled studies will be required to establish the clinical efficacy of PBM and to establish optimal stimulation parameters for cognitive impairment in schizophrenia. In addition, the assumptions underlying the sample size calculation were based on related intervention studies due to the limited availability of PBM trials targeting cognition and should therefore be interpreted with caution.

Conclusion

This exploratory study protocol aims to evaluate the safety, tolerability, and potential therapeutic effects of transcranial and intranasal PBM in individuals with CIS. Given the open-label single-arm design, definitive conclusions regarding clinical efficacy cannot be drawn and any findings should be interpreted cautiously.

Nevertheless, this study will provide preliminary clinical evidence regarding the safety and tolerability of PBM in Japanese patients with schizophrenia and may offer important insights for the design of future controlled trials. The data obtained may also serve as a foundation for large-scale studies aimed at evaluating clinical efficacy and optimizing stimulation parameters.