Roflumilast + TMS for Brain Plasticity

Overseen By Alexander McGirr, MD PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Calgary

Must not be taking: Roflumilast interactors

Disqualifiers: Epilepsy, Stroke, Renal, Liver, others

Stay on Your Current Meds You can continue your current medications while participating

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2.5 hours per session, separated by at least 1 week

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that have serious interactions with roflumilast, such as abametapir, apalutamide, and others listed in the exclusion criteria. If you are on any of these medications, you would need to stop them to participate.

What data supports the effectiveness of the treatment Roflumilast + TMS for Brain Plasticity?

Research shows that repetitive transcranial magnetic stimulation (rTMS) can help improve motor and psychological symptoms in conditions like stroke and traumatic brain injury by promoting brain plasticity (the brain's ability to change and adapt). While specific data on Roflumilast combined with TMS is not available, the effectiveness of rTMS in enhancing brain function suggests potential benefits when used with other treatments. ^{1 2 3 4 5}

Is the combination of Roflumilast and TMS generally safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) is generally safe, but some people may experience side effects like headaches or discomfort. Roflumilast, also known as Daliresp or Zoryve, is a medication used for other conditions and is generally considered safe, but it can have side effects like nausea or diarrhea. Always consult with a healthcare provider for personalized advice. ^{6 7 8 9 10}

How is the treatment Roflumilast + TMS unique for brain plasticity?

Roflumilast + TMS is unique because it combines a drug known for reducing inflammation with a non-invasive brain stimulation technique (TMS) that can target deep brain areas, potentially enhancing brain plasticity in ways other treatments do not. ^{8 10 11 12 13}

What is the purpose of this trial?

Repetitive transcranial magnetic stimulation (rTMS) uses a magnetic field to non-invasively induce electrical function within the brain. Stimulation allows brain cells to change the way that they adapt and communicate with each other, known as 'synaptic plasticity'. It is thought that alterations in these adaptive brain changes underlie the ability of rTMS to treat mental illnesses like depression. The regulation of synaptic plasticity is complex, and involves multiple interacting factors and redundant systems to ensure that plasticity is carefully regulated. To date, studies attempting to alter impact synaptic plasticity have done so using pharmacological adjuncts that target extracellular contributions to plasticity. Here, we propose the first proof of principle study targeting intracellular regulation of plasticity by using a pharmacological adjunct targeting Phosphodiesterase 4 (PDE4), a key regulator a cyclic AMP gradients in brain cells. We will pair TMS with electromyography (EMG) to measure activity dependent changes in the motor cortex following rTMS to test the ability of a PDE4 inhibition to enhance synaptic plasticity after rTMS.

Eligibility Criteria

This trial is for individuals interested in participating in a study on brain plasticity. Specific eligibility criteria are not provided, but typically participants would be healthy adults or those with conditions affecting brain function who meet inclusion and exclusion criteria set by the researchers.

Inclusion Criteria

Healthy individuals (no chronic medical conditions)

Exclusion Criteria

Current psychiatric concerns

Lactation

Allergy to roflumilast or any of its non-medicinal ingredients

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 visit

Treatment

Participants receive either roflumilast or placebo followed by theta-burst stimulation to the primary motor cortex

2.5 hours per session, separated by at least 1 week

Multiple sessions (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Roflumilast

Trial Overview The study tests if Roflumilast, a drug that targets intracellular regulation of synaptic plasticity, can enhance the effects of two types of transcranial magnetic stimulation (TMS) on motor cortex activity compared to placebo.

Participant Groups

Group I: Intermittent Theta-Burst Stimulation with Roflumilast Experimental Treatment 2 Interventions

Intermittent theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested roflumilast 500mcg.

Group II: Continuous Theta-Burst Stimulation with Roflumilast Experimental Treatment 2 Interventions

Continuous theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested roflumilast 500mcg.

Group III: Intermittent Theta-Burst Stimulation with Placebo Placebo Group 2 Interventions

Intermittent theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested a placebo.

Group IV: Continuous Theta-Burst Stimulation with Placebo Placebo Group 2 Interventions

Continuous theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested a placebo.

Roflumilast is already approved in United States, European Union for the following indications:

Approved in United States as Daliresp for:

• Chronic Obstructive Pulmonary Disease (COPD)
• Plaque Psoriasis
• Seborrheic Dermatitis

Approved in European Union as Daliresp for:

• Chronic Obstructive Pulmonary Disease (COPD)

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Findings from Research

In a chronic stroke patient, 5 days of low-frequency rTMS on the intact motor cortex led to improvements in motor function and neuropsychological symptoms without any adverse effects.

Neuroimaging revealed that these improvements were linked to changes in brain activity, specifically a reduction in hyperactivity and reorganization in the opposite hemisphere, suggesting a mechanism of neuroplasticity that supports recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioral and neuroplastic effects of low-frequency rTMS of the unaffected hemisphere in a chronic stroke patient: a concomitant TMS and fMRI study. Salatino, A., Berra, E., Troni, W., et al.[2014]

A study involving 97 participants, including 58 individuals with traumatic brain injury (TBI), suggests that using multimodal neuroimaging to customize transcranial magnetic stimulation (TMS) treatments is feasible and may enhance treatment effectiveness.

The research indicates that TBI is a complex condition with varying anatomical features, and tailoring TMS based on neuroimaging data could help in understanding and improving treatment outcomes for individuals with TBI and co-occurring conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Customizing TMS Applications in Traumatic Brain Injury Using Neuroimaging. Herrold, AA., Siddiqi, SH., Livengood, SL., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) significantly improved both depressive and cognitive symptoms in 33 patients with treatment-resistant depression (TRD) after 20 sessions of treatment.

While rTMS treatment increased serum levels of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), these changes were associated with symptom improvement but not significantly, suggesting rTMS may help normalize these neurotrophic factors in TRD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotrophic Factor Levels and Cognitive Functions before and after the Repetitive Transcranial Magnetic Stimulation in Treatment Resistant Depression. Demiroz, D., Cicek, IE., Kurku, H., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) significantly reduces neuropathic pain in traumatic brain injury (TBI) patients, with a mean difference of -1.00, indicating its potential as an effective treatment.

rTMS also shows promise in improving depression and post-concussion symptoms, particularly with 1 Hz stimulation over the right dorsolateral prefrontal cortex, although its effects on cognition remain unclear and no major adverse events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for Neuropathic Pain and Neuropsychiatric Symptoms in Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Li, X., Lu, T., Yu, H., et al.[2022]

In a study involving 34 Alzheimer's disease patients, those receiving combined repetitive transcranial magnetic stimulation (rTMS) and cognitive training showed significant cognitive improvements compared to those receiving sham treatments.

The study found that baseline measures of brain plasticity predicted cognitive improvements after treatment, suggesting that rTMS may enhance brain function and support cognitive training in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Corticomotor Plasticity Predicts Clinical Efficacy of Combined Neuromodulation and Cognitive Training in Alzheimer's Disease. Brem, AK., Di Iorio, R., Fried, PJ., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) is generally safe for older adults with late-life depression, with only 12.4% reporting any adverse events and serious adverse events occurring in just 1.5% of cases, based on a review of 11 studies involving 353 patients.

The most common adverse events were mild, such as headaches (6.9%) and discomfort at the stimulation site (2.7%), although some serious adverse events, including psychiatric hospitalization and increased suicidal ideation, were noted in case reports, highlighting the need for further research to ensure safety in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. Overvliet, GM., Jansen, RAC., van Balkom, AJLM., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) was found to be safe for a patient with an implanted subdural cortical electrode, showing no serious adverse effects during treatment.

Ex-vivo experiments indicated that rTMS caused only a slight increase in coil temperature and no displacement of the electrodes, suggesting that rTMS can be safely applied in clinical settings for patients with such implants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case. Phielipp, NM., Saha, U., Sankar, T., et al.[2019]

High-frequency repetitive transcranial magnetic stimulation (rTMS) is effective in treating treatment-resistant depression, as demonstrated in a patient who improved after multiple sessions.

Despite experiencing a seizure during the fourth rTMS session, the patient was safely treated with the antiepileptic drug valproate, allowing for continued rTMS sessions without further seizures and leading to improvement in his depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation safely administered after seizure. Bagati, D., Mittal, S., Praharaj, SK., et al.[2013]

In a randomized controlled trial involving 142 patients, daily left prefrontal rTMS showed a significant 37% reduction in procedural pain over 15 sessions, indicating that patients may adapt to the treatment's discomfort over time.

The decrease in pain was specific to those receiving active rTMS and suggests that the stimulation itself may contribute to pain reduction, rather than just patient accommodation, which could be linked to improved clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The painfulness of active, but not sham, transcranial magnetic stimulation decreases rapidly over time: results from the double-blind phase of the OPT-TMS Trial. Borckardt, JJ., Nahas, ZH., Teal, J., et al.[2021]

This case report demonstrates that therapeutic repetitive transcranial magnetic stimulation (rTMS) can be safely administered to a patient with a brain lesion and recurrent major depression, with no seizures occurring during treatment.

The patient experienced remission from depression after 36 sessions of rTMS over 6 weeks, with only mild side effects like transient headaches, indicating rTMS is a potentially effective treatment option even in complex medical cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depression in a Patient With an Intracranial Space-Occupying Lesion: A Case Report of Safety. Surya, S., Rosenquist, PB., McCall, WV.[2018]

In a young adult with drug-resistant bilateral temporal lobe epilepsy, low frequency repetitive TMS (rTMS) using specially designed H-coils significantly reduced seizure frequency by 50 to 70% after three treatment courses of varying lengths (10, 15, and 30 sessions).

The rTMS treatment was well-tolerated, indicating it is a safe option for patients who do not respond to conventional epilepsy medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

H-coil repetitive transcranial magnetic stimulation for treatment of temporal lobe epilepsy: A case report. Gersner, R., Oberman, L., Sanchez, MJ., et al.[2020]

In a study involving 60 inpatients with treatment-resistant depression, both 1 Hz rTMS and venlafaxine ER showed similar efficacy in reducing depressive symptoms, with no significant differences in outcomes measured by the MADRS, BDI-SF, and CGI scales.

Both treatments resulted in clinically relevant reductions in depression scores, indicating that rTMS can be an effective alternative to traditional antidepressants like venlafaxine for patients who have not responded to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low frequency (1-Hz), right prefrontal repetitive transcranial magnetic stimulation (rTMS) compared with venlafaxine ER in the treatment of resistant depression: a double-blind, single-centre, randomized study. Bares, M., Kopecek, M., Novak, T., et al.[2015]

High frequency repetitive transcranial magnetic stimulation (hf-rTMS) was well-tolerated in a patient with logopenic primary progressive aphasia (LPPA) due to Alzheimer's disease, showing promising safety for this treatment.

After one month of hf-rTMS, the patient exhibited significant improvements in linguistic and cognitive skills, suggesting that hf-rTMS may have a lasting positive effect on cognitive function in LPPA patients, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Left Prefrontal Repetitive Transcranial Magnetic Stimulation in a Logopenic Variant of Primary Progressive Aphasia: A Case Report. Bereau, M., Magnin, E., Nicolier, M., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Behavioral and neuroplastic effects of low-frequency rTMS of the unaffected hemisphere in a chronic stroke patient: a concomitant TMS and fMRI study. [2014]

2. United States pubmed.ncbi.nlm.nih.gov

Customizing TMS Applications in Traumatic Brain Injury Using Neuroimaging. [2021]

3. Pakistan pubmed.ncbi.nlm.nih.gov

Neurotrophic Factor Levels and Cognitive Functions before and after the Repetitive Transcranial Magnetic Stimulation in Treatment Resistant Depression. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for Neuropathic Pain and Neuropsychiatric Symptoms in Traumatic Brain Injury: A Systematic Review and Meta-Analysis. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Corticomotor Plasticity Predicts Clinical Efficacy of Combined Neuromodulation and Cognitive Training in Alzheimer's Disease. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation safely administered after seizure. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

The painfulness of active, but not sham, transcranial magnetic stimulation decreases rapidly over time: results from the double-blind phase of the OPT-TMS Trial. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depression in a Patient With an Intracranial Space-Occupying Lesion: A Case Report of Safety. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

H-coil repetitive transcranial magnetic stimulation for treatment of temporal lobe epilepsy: A case report. [2020]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Low frequency (1-Hz), right prefrontal repetitive transcranial magnetic stimulation (rTMS) compared with venlafaxine ER in the treatment of resistant depression: a double-blind, single-centre, randomized study. [2015]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Left Prefrontal Repetitive Transcranial Magnetic Stimulation in a Logopenic Variant of Primary Progressive Aphasia: A Case Report. [2018]