Innovative Digital and Neuromodulation Interventions for Mood Disorders

1. mHealth Physical Activity Intervention for Depression – The MoodMover App

Physical activity is widely recognized as a modifiable lifestyle factor that can improve mood and alleviate depressive symptoms. However, individuals with depression often struggle with maintaining regular PA due to reduced motivation, low energy, and other emotional barriers. In response to this treatment gap, researchers have developed MoodMover—a 9‑week app-based PA intervention designed specifically for people with depression.

Development Framework and Theoretical Underpinnings

The development of MoodMover followed the early stages of the Integrate, Design, Assess, and Share (IDEAS) framework. This process involved:

Identifying intervention needs and planning: A comprehensive systematic review revealed that very few digital PA interventions were tailored for people with depression. Given the increasing prevalence of depression and the high smartphone ownership rate, a mobile app was considered a promising modality.
Intervention content guided by theory: Instead of relying solely on traditional social cognitive theories, the Multi‑Process Action Control (M‑PAC) framework was chosen. M‑PAC highlights the phases of intention formation, translation into behavior, and long‑term habit and identity development. This model incorporates reflective processes (instrumental and affective attitudes, perceived capability, and perceived opportunity) and regulatory processes (action planning, coping strategies, self‑monitoring, and habit formation). For individuals with depression, particular emphasis was given to affective attitudes, perceived capability, and action regulation.
Iterative Prototyping and Usability Testing: A multidisciplinary team adapted content from an existing web‑based PA intervention and translated it into a mobile-friendly format using a “no‑code” platform. The app incorporates diverse multimedia content (text, images, videos, and podcasts), gamification elements (points redeemed for e‑gift cards), and features such as a step tracker, goal setting, and mood tracking. Iterative usability testing using a standardized mHealth App Usability Questionnaire (MAUQ) revealed average domain scores above 5 (on a 7‑point Likert scale), indicating good to high usability.

MoodMover Intervention Content Overview

Below is a summary table of the major modules in MoodMover, the M‑PAC constructs targeted, and the corresponding behavior change techniques (BCTs) employed:

Module	Major Topics Covered	Targeted M‑PAC Constructs	Behavior Change Techniques (BCTs)
1. Feeling Better Through Daily Activity	Role of exercise as a treatment for depression; interaction of mood and PA; physical benefits of exercise	Affective attitudes, instrumental attitudes; initial regulation	Information about health consequences; goal setting; self-monitoring
2. Making Physical Activity Enjoyable	Strategies to enhance enjoyment of PA	Affective attitudes; behavioral regulation	Information about emotional consequences; behavioral practice/rehearsal; self-monitoring
3. Building Your Self‑Confidence	Increasing self‑efficacy; learning from peer exercise experiences	Perceived capability; action regulation	Goal setting; self-monitoring; social comparison
4. Creating Opportunities for PA	Environmental factors influencing PA; “grab and go” strategies; identifying opportunities	Perceived opportunity; planning	Prompts/cues; restructuring the physical environment
5. Developing Self‑Regulatory Skills	Action and coping planning; overcoming barriers	Behavioral regulation; planning and problem solving	Action planning; problem solving; self-monitoring
6. Drawing on Social Support	Building a supportive network; strategies for encouragement	Social support; regulation	Social support (practical and emotional); self-talk
7. Forming an Exercise Habit	Relation of habit to sustained PA; strategies for routine development	Habit formation; reflexive processes	Habit formation; repeated practice
8. Building an Exercise Identity	Aligning self‑concept with physical activity; internalizing a positive identity	Identity; self‑affirmation	Incompatible beliefs; identity shaping

Usability Testing Results

In a pilot usability test with nine participants (mean age approximately 38.4 years; majority diagnosed with major depressive disorder), the following key findings emerged:

Ease of Use: Participants rated the app highly for intuitiveness and ease of navigation. Minor issues (e.g., screen scrolling for longer content) were resolved by splitting content or providing additional instructional videos.
Content and Features: The graded goal-setting approach (increasing daily steps incrementally by 1,000 up to a target of 3,000 extra steps) was well received. Participants appreciated the integrated step tracker, mood self‑tracking after exercise sessions, and gamification through point incentives.
Overall Satisfaction: Quantitative assessment via MAUQ provided an overall mean usability score of 5.79 on a 7‑point scale.

2. Neuromodulation and Bio‑Resonance Technologies in Comorbid MDD and GAD

Despite numerous treatment options, patients with comorbid major depressive disorder (MDD) and generalized anxiety disorder (GAD) often exhibit resistance to conventional therapies. An exploratory pilot case series has investigated a novel intervention that combines dual hemispheric repetitive transcranial magnetic stimulation (rTMS) with bio‑resonance neurotechnology (BRNT) aimed at shifting autonomic balance towards parasympathetic dominance.

The Innovative Intervention

rTMS Component: The dual hemispheric rTMS targets the dorsolateral prefrontal cortex (DLPFC) bilaterally. This protocol—administered as standard “DASH” protocol—has been employed to modulate cortical excitability and has shown efficacy for treatment‑resistant depression.
BRNT Component: Prior to rTMS, participants receive 30 minutes of treatment with BRNT (NuCalm®), which utilizes neuro‑acoustic brainwave entrainment, electromagnetic frequency bio‑resonance, and light‑blocking. This combination is designed to reduce sympathetic nervous system overactivity and promote a parasympathetic state, thereby enhancing receptivity to rTMS.

Pilot Case Series – Patient Data

Three patients (two females and one male) with comorbid severe MDD and GAD were treated. The severity of symptoms was measured using the Patient Health Questionnaire‑9 (PHQ‑9) for depression and the Generalized Anxiety Disorder scale (GAD‑7) for anxiety.

Summary Table: Patient Demographics and Symptom Scores

Patient	Age	Diagnosis	Number of rTMS Sessions	PHQ‑9 (Pre)	PHQ‑9 (Post)	GAD‑7 (Pre)	GAD‑7 (Post)
1	47	MDD (severe, recurrent); GAD	60	27	1	21	0
2	32	MDD (severe, recurrent); GAD	36	20	2	21	2
3	45	MDD (severe, recurrent); GAD; PTSD	36	17	1	19	3

Statistical Findings: A paired t-test across subjects revealed a statistically significant decrease in PHQ‑9 scores (mean difference = 20 points; p ≈ 0.023 before correction, p ≈ 0.045 after Bonferroni correction) and in GAD‑7 scores (mean difference = 18.67 points; p ≈ 0.006 before correction, p ≈ 0.012 after correction). Effect sizes (Cohen’s d) were notably large for both measures (approximately 5.47 and 13.8 times the variability, respectively).

These results underscore the potential clinical benefit of combining rTMS with BRNT to treat complex mood and anxiety symptoms. However, larger, controlled, and sham‑controlled studies are required to validate these promising results.

3. Cerebrospinal Fluid Biomarkers and Brain Structural Changes in Bipolar Disorder

Bipolar disorder is associated not only with mood dysregulation but also with progressive structural brain changes. Emerging evidence suggests that central nervous system (CNS) inflammation plays a role in neuroprogression. A recent study investigated whether CSF inflammatory biomarkers can predict cortical decline and ventricular enlargement.

Study Overview

Participants: Individuals with bipolar disorder and healthy controls underwent magnetic resonance imaging (MRI) at two timepoints. Simultaneously, levels of inflammation‑related biomarkers (interleukin‑8 [IL‑8] and YKL‑40) were measured in the CSF.
Key Findings in Bipolar Disorder: In patients with bipolar disorder, higher baseline CSF IL‑8 levels were significantly associated with a decline in cortical thickness in the left and right middle temporal cortex and right inferior frontal gyrus.
Findings in Healthy Controls: Among healthy controls, elevated baseline CSF levels of YKL‑40 predicted increased ventricular volume (enlargement) over time.

Summary Table: CSF Biomarker Associations in Bipolar Disorder and Healthy Controls

Group	Biomarker	Target Brain Region(s)	Association
Bipolar Disorder	IL‑8	Left and right middle temporal cortex; right inferior frontal gyrus	Higher IL‑8 predicts significant cortical thinning over time
Healthy Controls	YKL‑40	Lateral ventricles (both hemispheres)	Higher YKL‑40 predicts significant ventricular enlargement

These findings highlight the importance of CNS inflammation in the neuroprogression of bipolar disorder and also in the normal process of brain aging. The lack of significant associations with serum biomarkers further reinforces the relevance of CSF-derived markers for understanding brain-specific inflammatory processes.

4. Discussion and Integration

The three innovative approaches detailed above demonstrate the promise of integrating digital health and neuromodulation techniques with biological biomarker assessments to improve outcomes in mood disorders. Digital interventions such as MoodMover provide a scalable, user‑centered platform to increase physical activity—a modifiable factor known to alleviate depressive symptoms. Simultaneously, the pilot case series employing dual hemispheric rTMS combined with BRNT offers an intriguing multimodal treatment option for patients with comorbid MDD and GAD who are resistant to conventional therapies. Finally, the study of CSF inflammatory biomarkers not only advances our knowledge of the brain’s inflammatory state in bipolar disorder but also highlights potential biomarkers for tracking neuroprogression.

These approaches are complementary. While digital tools can empower patients to adopt healthier behaviors independently, neuromodulation techniques and biomarker assessments may provide the personalized neurobiological data needed to tailor and optimize intervention protocols. Future research that combines these modalities may help clinicians refine treatment strategies and facilitate earlier intervention for mood disorders, ultimately impacting patient quality of life and reducing the overall public health burden.

Frequently Asked Questions (FAQ)

What is the main purpose of the MoodMover app?
A1. The MoodMover app is designed to promote physical activity among individuals with depression by using a graded, theoretically informed intervention rooted in the M‑PAC framework. It incorporates features such as goal‑setting, step tracking, mood self‑monitoring, and gamification to enhance user engagement and help improve depressive symptoms.

How do rTMS and BRNT work together to treat comorbid MDD and GAD?
A2. In the combined treatment strategy, dual hemispheric rTMS targets the dorsolateral prefrontal cortex to modulate cortical activity associated with mood regulation. BRNT, delivered prior to rTMS, employs neuro‑acoustic rhythms, electromagnetic frequency bio‑resonance, and light‑blocking to shift the autonomic balance toward a parasympathetic (relaxed) state. This preconditioning may enhance the effectiveness of rTMS in reducing symptoms of depression and anxiety.

Why are CSF biomarkers important in bipolar disorder research?
A3. CSF biomarkers, such as IL‑8 and YKL‑40, provide direct insight into central nervous system inflammation. Their association with structural brain changes (cortical thinning and ventricular enlargement) in bipolar disorder can serve as objective markers of neuroprogression, thereby helping in tracking disease progression and potentially guiding personalized treatment strategies.

Can these interventions replace conventional pharmacotherapy?
A4. Although these innovative interventions show promising results, they are currently considered as adjuncts or alternatives for individuals who have not achieved optimal outcomes with conventional therapies. Further large‑scale, controlled studies are necessary to determine their place in treatment guidelines.

How do the usability findings of MoodMover impact its potential success?
A5. The high usability scores obtained through standardized measures (with MAUQ scores above 5 on a 7‑point scale) indicate that patients find the app accessible and engaging. This is critical because sustained user engagement is essential for medRxiv interventions to have a positive effect on behavior change and mental health outcomes.

References

Tang, Y., Gierc, M., La, H., Kim, J., Liu, S., Lam, R. W., Puterman, E., & Faulkner, G. (2025). MoodMover: Development and usability testing of an mHealth physical activity intervention for depression. Digital Health
Sunder, K., Makale, M. T., Miles, M., Bodhanapati, J., Murphy, K. T., Dennen, C. A., Baron, D., Thanos, P. K., Hanna, C., & Ashford, J. W. (2025). Coupling bio‑resonance neurotechnology (BRNT) and dual hemispheric repetitive transcranial magnetic stimulation (rTMS) reduces comorbid major depressive disorder (MDD) and generalized anxiety disorder (GAD) as demonstrated by PHQ‑9 and GAD‑7: Pilot case series. Psychology Research and Behavior Management. https://pubmed.ncbi.nlm.nih.gov/11797920/
[Neuropsychobiology Study]. (2024). Cerebrospinal fluid biomarkers of central nervous system inflammation predict cortical decline in bipolar disorder and ventricular enlargement in healthy controls. Neuropsychobiology. https://pubmed.ncbi.nlm.nih.gov/11797920/