Conventional Repetitive Transcranial Magnetic Stimulation for Depression: A Step-by-Step Protocol

Resumo

This protocol presents a guide for the precise and patient-centered application of repetitive transcranial magnetic stimulation for treatment-resistant major depression. Details are provided on procedures for accurate coil localization, adjustable stimulus dosing, rigorous safety measures, and strategies that maximize comfort, reproducibility, and long-term clinical effectiveness across acute and maintenance sessions.

Resumo

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive approach for brain stimulation, with proven effectiveness and efficacy to treat Major Depressive Disorder (MDD), particularly for episodes that do not respond to antidepressant medication. A structured patient-centered Transcranial Magnetic Stimulation (TMS) protocol, focused on precision, comfort, and safety, should be provided in TMS clinics treating MDD. The procedure begins with the patient seated comfortably in a reclining chair, equipped with head and foot support. A pillow is placed around the patient's neck to ensure head stability and comfort throughout the session. A lycra cap is placed on the patient's head, and the treatment area is marked on the cap to ensure the correct placement of the electromagnetic coil. Two main strategies, relying on the head landmarks for each individual patient, have been widely used to identify the treatment area: the 5 cm rule and the Beam F3 method. To initiate the treatment, the coil is positioned on the treatment target to deliver a series of electromagnetic pulses. Patients hear a clicking sound and feel a light tapping sensation on the scalp. For acoustic protection, earplugs are provided before the session begins. The stimulation itself typically causes no discomfort, and patients can resume their normal daily activities after the session. However, driving is discouraged immediately after treatment sessions. The rTMS protocol to treat MDD consists of 20 to 30 daily sessions over four to six weeks, monitored by regular consultations with a psychiatrist, to track progress and adjust if needed. Maintenance sessions may follow to sustain clinical benefits. This step-by-step protocol ensures comfort, consistency, and effective treatment delivery for patients undergoing rTMS therapy.

Introdução

Transcranial Magnetic Stimulation (TMS) is a non-invasive neuromodulation technique based on the principle of electromagnetic induction¹. If an electric current passes through a TMS coil, it generates an electromagnetic field perpendicular to the current's direction¹. When this field interacts with conductive material, such as neural tissue, it induces electrical activity¹. This enables targeted modulation of neuronal activity in discrete regions of the cerebral cortex, opening new avenues for both neuroscientific research and clinical applications². The evolution of TMS technology led to the development of repetitive TMS (rTMS), involving the delivery of repeated electromagnetic pulses to a target cortical region at a predetermined frequency³. High-frequency rTMS (≥ 5 Hz) typically facilitates cortical excitability, whereas low-frequency rTMS (≤ 1 Hz) suppresses it³. More complex protocols for rTMS, such as intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), also allow for modulation of brain activity and have been integrated into clinical practice³.

The therapeutic potential of rTMS for psychiatric disorders was first explored in the 1990s, with studies demonstrating its effects in patients with medication-resistant depression^4,5. Since then, numerous clinical trials and meta-analyses have established rTMS as a safe and effective treatment for neuropsychiatric disorders⁶. In 2008, the U.S. Food and Drug Administration (FDA) cleared high-frequency rTMS for episodes of treatment-resistant depression (TRD)^7,8,9,10, marking the first official neuropsychiatric application of the technique¹¹. Subsequent regulatory decisions followed, including clearance of iTBS for TRD in 2018, following evidence of equivalent efficacy to the conventional TMS protocol, and of rTMS for obsessive-compulsive disorder (OCD) in 2019, as well as designation of rTMS as a breakthrough therapy for bipolar depression¹¹. The European regulatory framework, through the Conformité Européenne (CE) Mark, has similarly certified multiple TMS devices and protocols for clinical use¹¹.

Evidence-based recommendations from expert consensus and clinical guidelines have reinforced the therapeutic role of rTMS in depression¹². Robust clinical data support its efficacy in TRD, with response rates ranging from 39.5% to 70% and remission rates between 16.6% and 76.9%¹³. Importantly, the antidepressant effects of TMS have been shown to persist, with 53% of responders maintaining improvements at six months and 46% at one-year post-treatment¹⁴. The left dorsolateral prefrontal cortex (L-DLPFC) is the cleared target for depression treatment, though alternative protocols involving right DLPFC stimulation or bilateral approaches have also been explored¹⁵. Conventional treatments offer daily stimulation sessions across several weeks, while more recent accelerated protocols have been developed with multiple sessions per day for a shorter period¹⁶. In this work, adding to existing guidelines¹⁷, we aim to provide a step-by-step guide for application of conventional rTMS to treat a major depressive episode, incorporating elements such as structured ramping strategies, predefined psychometric assessment timelines, and detailed comfort and safety measures, within a clinical setting that ensures consistency, effective treatment delivery, and adherence to regulatory clearances or recommendations¹¹. Hence, we aim to provide guidance for clinical application of TMS to treat depression, towards mitigating variability in application of treatments, while improving tolerability, consistency, and real-world implementation.

Protocolo

This protocol provides a standardized approach to treating depression using a conventional protocol for Transcranial Magnetic Stimulation (TMS). TMS sessions are categorized into three types: First Session, Regular Sessions, and Assessment Sessions. Procedures of this protocol are performed at the Champalimaud Foundation using a MagVenture MagPro X100 magnetic stimulator, with a Cool-B65 figure-of-eight coil. SINGER safety Ear Plugs B38 are provided to all participants and TMS technicians.

1. Prescription of TMS (performed by prescribing physician)

1. Assess eligibility for TMS treatment during clinical interview, detailing current and past medical history:
   1. Confirm diagnosis of current major depressive episode for approved use.
   2. Screen for risk of side-effects (e.g., seizures) and treatment contraindications^17,18. Absolute contraindications to rTMS are the presence of electronic or metallic implants in the brain. While not absolute reasons to withhold treatment, careful risk-benefit assessment is required in cases of uncontrolled active medical illness requiring immediate attention, electronic or metallic implants in the body that are not compatible with electromagnetic fields, epilepsy, pregnancy, breastfeeding, women planning pregnancy, and psychotic or mood disorders requiring immediate hospitalization.
2. Obtain informed consent clearly explaining procedures, risks, including seizures, and any off-label use^17,18.
3. Prescribe TMS in a shared decision-making process with the patient, considering approved, off-label, and emerging indications¹¹.

2. TMS clinic and staff

1. Use equipment with regulatory clearance, including the TMS stimulator, the TMS coil, and the TMS cooling system.
2. Have life-support and emergency plans for syncope and seizures^19,20.
3. Ensure all staff are trained in TMS mechanisms, risks, and emergency management, with at least basic life support skills^17,18,21.
4. Include a licensed physician who supervises treatment, who must be accessible, at least by phone, during sessions^17,18,21.

3. First TMS session

1. Arrival and administrative check-in (administrative staff)
   1. Greet the patient upon arrival at the TMS Clinic.
   2. Confirm necessary documentation for admission, including TMS prescription, completed informed consent documentation, and safety check.
   3. Introduce the patient to the TMS technician.
      1. Have the TMS technician explain the general procedures.
      2. Provide the patient with a clipboard containing the following assessment materials to evaluate sociodemographic variables and collect self-reported psychometric data (by TMS technician). i) Sociodemographic questionnaire: Self-report questionnaire to collect information such as age, gender, education, occupation, handedness, mode of transport to and from treatment, and habits, among others, found relevant for each specific context. ii) Beck Depression Inventory-II (BDI-II): A 20-item scale that assesses the severity of depressive symptoms, completed by the patient²². Other self-report scales to assess depression severity are available. It is recommended that at least one self-report scale should include one or more items to assess suicidal ideation and/or intent. iii) Visual Analog Scale (VAS): A 10 cm line used to assess the patient's mood, where 0 represents the worst possible mood and 10 represents the best possible mood.
2. Pre-session device check (by TMS technician)
   1. Verify and confirm the integrity of the stimulator and coil.
   2. Confirm integrity of active cooling (if applicable).
      NOTE: Routine technical inspection and calibration of the TMS device are recommended. The service schedule should follow the manufacturer's guidelines and may vary depending on the age and condition of the equipment. Consult the device provider for specific recommendations.
3. Introduction to TMS (by TMS technician)
   1. Call the patient to the treatment room. Normally, the session is conducted with only the technician and the patient. Upon explicit consent from the patient, chaperones (e.g., family members) or trainees may be present.
   2. Introduce the TMS technique, including an explanation of known mechanisms of action in lay terms.
   3. Discuss potential side effects²³.
4. Demonstration (by TMS technician):
   1. Invite the patient to experience the stimulation on the forearm, ensuring the coil is positioned correctly and that the patient is informed about the brief tapping or tingling sensation.
   2. Demonstrate the sensation of TMS on the patient's forearm, usually the inner side, midway between the wrist and elbow, using a single pulse at low intensity (e.g., 30-40% of maximum stimulator output).
      NOTE: This familiarization step helps reduce anxiety, build rapport, and increase comfort during the procedure. Avoid this demonstration in patients with electronic implants (e.g., pacemakers, neurostimulators) or in pregnant women. While peripheral exposure to electromagnetic fields is considered safe, it may pose theoretical risks¹⁸. In such cases, use verbal explanation and reassurance instead of direct stimulation, or stimulate a different region, farther from the electric device or the abdomen (e.g., ankle).
5. Clinical interviews (by TMS technician): Conduct semi-structured clinical interviews to assess the severity of symptoms. Psychometric instruments serve to establish baseline parameters to monitor treatment progress. The following are two examples of clinician-administered scales:
   1. Montgomery-Asberg Depression Rating Scale (MADRS): Use it to evaluate the severity of depressive symptoms²⁴. MADRS (and BDI-II) can be used to assist in assessing treatment outcome. While the definitive assessment of outcome is performed collaboratively by the patient and the prescribing physician, quantitative definitions of response and remission are relatively consensual in the available literature²⁵.
      NOTE: A partial responder is defined as a patient who experiences at least 25% reduction in depressive symptoms, while a full responder has 50% reduction or more. These definitions are used in both clinical and research settings²⁴. Remission is defined as the state in which depressive symptoms have been reduced to a level considered within the normal range, indicating near or complete resolution of the depressive episode, usually operationalized as a total score below an instrument-specific threshold (e.g., MADRS ≤ 10)^16,26.
   2. Young Mania Rating Scale (YMRS): Use it to evaluate the severity of manic or hypomanic symptoms. Mania is a concern among patients with a known diagnosis of bipolar disorder, but it can also occur in patients without a previous diagnosis of bipolar disorder. Scales such as the YMRS are used to monitor the occurrence of mania as a potential side-effect of treatment.
      NOTE: Once baseline assessments are completed, the TMS technician initiates all procedures that require the use of the TMS device. Clinical assessments are repeated at variable intervals depending on available resources and patient needs. Self-report scales and/or clinical interviews are repeated at least after TMS sessions have been completed, to assist in the assessment of response to treatment.

4. Full TMS procedures (performed by TMS technician)

NOTE: Full TMS procedures, including determination of the motor threshold, are performed in the first TMS session and can be repeated at variable intervals across TMS centers depending on available resources and patient needs. Some centers conduct a single full session at the beginning of the acute TMS treatment phase, while others perform all assessments daily^17,27. An evidence-based approach is to repeat all assessments every five sessions (i.e., weekly), typically at sessions 6, 11, 16, 21, 26, to allow for the definition of TMS intensity for the following week²⁷.

1. Initial procedures: Systems using helmet-like coils¹¹ have a particular protocol, described in detail by Feifel and Pappas²⁸. The following steps are used for TMS systems with figure-of-eight coils, which are predominant in most countries.
   1. Place a lycra cap on the patient to mark areas of interest on the scalp. Confirm the cap is aligned according to the patient's eyebrows and the upper part of the ears, ensuring consistent reference points for cap placement in subsequent sessions.
   2. Provide earplugs to the patient to minimize discomfort from the stimulation sounds. Use your own earplugs during TMS procedures.
   3. Register these procedures in the patient's clinical chart.
2. Determining the motor hotspot: This step involves identifying the stimulation hotspot for the primary motor cortex (MH) of the hand region in the left hemisphere.
   1. Use a measuring tape to determine and mark the mid-sagittal line, extending from the nasion (the top of the nose bridge) to the inion (the prominent bump at the back of the skull).
   2. Mark the intertragus line by placing one end of the tape at one tragus (point just in front of the ear) and stretching it across to the other side.
   3. Consider the intersection of these two lines as the cranial vertex, from which additional measurements are taken to locate the motor cortex hotspot.
   4. Mark a triangle by extending a line 5 cm to the left along the intertragus line and 5 cm anteriorly along the mid-sagittal line, both starting at the cranial vertex. The third side is drawn diagonally to link the free extremities of the first 2 lines. The reference point to initiate the search for the hand motor hotspot search is located 2.5 cm along the diagonal line, measured from the left-most vertex of the triangle.
   5. Mark 4 additional points positioned 0.5 cm anterior, posterior, lateral, and medial from this reference point to facilitate exploration.
   6. Use the above 5 points as locations where the anterior edge of the TMS coil is placed during the motor hotspot detection procedure.
   7. To start the motor hotspot search, instruct the patient to rest the arms and hands on the armrests of the chair or on his/her lap, ensuring they are visible and relaxed.
   8. Place the handle of the figure-of-eight TMS coil on the head of the patient at a 45° angle relative to the sagittal midline (handle directed posteriorly and to the left).
   9. Apply pulses maintaining the coil in the position mentioned above. To familiarize the patient with the procedure, deliver initial pulses at lower intensities (e.g., 20-30%), while assessing patient's sensory experience. Confirm visible muscle contraction of the contralateral hand muscles.
      1. If no motor response is observed at these initial intensities in the marked reference points from the previous step, increase the stimulation intensity in 5% increments until a motor response is elicited, defined as a visible contraction of the right hand (i.e., the hand contralateral to the stimulated hemisphere).
         NOTE: Depending on the patients' anatomy, the TMS technician aims to determine specifically the area responsible for muscle contraction of the abductor pollicis brevis and/or first digit interosseus (contraction of the first two digits)^29,30.
      2. Once a motor response is detected, explore the several marked reference points to identify the site where the motor response is maximal.
      3. Mark and use additional reference points as needed, at different cardinal positions and/or spaced more than 0.5 cm (e.g., 1cm). The hotspot is the location where the contraction exhibits the highest magnitude.
      4. Once the optimal stimulation site is identified, trace a concave line following the anterior edge of the coil and mark the center of this line.
   10. Confirm MH at regular intervals. If MH refinement is necessary during a session or during a treatment cycle, mark the new MH in the patient's cap and register the reason for refinement in the clinical chart, as per protocol (e.g., weekly MH assessments) or due to another reason.
3. Resting motor threshold (rMT) determination: After finding the MH, assess the rMT. This is the minimum dose required to elicit a contraction of the hand in at least 5 out of 10 pulses delivered to the MH.
   1. Begin this process after an accommodation period.
   2. Deliver pulses at 50% of the machine's maximum intensity. Confirm that a visible muscle contraction of the contralateral hand muscles is occurring at least 5 out of 10 pulses.
      1. If a hand contraction is not elicited in at least 5 out of 10 pulses, increase the intensity by 2% points until this is achieved.
      2. If this occurs, decrease the intensity by 1% until the minimum intensity that elicits a motor response is found, considering the criterion of a response in at least 5 out of 10 pulses.
   3. Register rMT in the patient's clinical chart for further use in the following sessions.
   4. If rMT re-assessment is necessary during the session or during the treatment cycle, register the new rMT and the reason for re-assessment, namely per protocol (e.g., weekly rMT assessments) or due to an unexpected reason (e.g., change in medication that potentially impacts rMT).
      NOTE: This procedure is tailored for TMS devices where stimulation intensity is expressed as a percentage of the device's maximum output. For devices that represent intensity using different units, appropriate adaptations are made.
4. Treatment site (TS) determination: After identifying the MH and determining the rMT, proceed to locate the TS. There are several methods to determine the TS including neuronavigated methods, as described by Dunlop et al.³¹. Here, the focus is on non-neuronavigated approaches, which rely on scalp-based measurements and have been widely utilized and supported in clinical practice¹⁷. Two methods have been advocated: the 5 cm-rule and Beam F3.
   1. 5 cm rule: From the midpoint of the concave line drawn after determining the motor hotspot, extend a para-sagittal line anteriorly and mark the stimulation spot for the left DLPFC at 5-6 cm (most frequently 5.5 cm) on this line.
   2. Beam F3: Use this strategy to locate the F3 position of the 10-20 electroencephalogram system on the scalp, an alternative landmark for the L-DLPFC. Input specific patient's head measurements into a freely available computer software that provides instructions to mark F3 in accordance with the patient's head size (see Table of Materials)³².
      1. Obtain 3 measurements using a tape measure: i) Measure the nasion-inion distance from the nasion (the top of the nose bridge) to the inion (the prominence at the back of the skull). ii) Measure the intertragus distance from the left to the right tragus. iii) Measure the head circumference by passing the tape measure over the inion at the level of the eyebrows.
      2. Input these measures in the software interface to generate two outputs. First, the distance to the left of the midline along the head circumference (Point X). Second, the distance from the vertex along a line intersecting Point X (Point Y). Point Y is the L-DLPFC TS as determined by the Beam F3 method. Use these two distances to mark the TS.
   3. Determine TS at regular intervals. If TS refinement is necessary during the session or during the treatment cycle, mark the new TS on the patient's cap and register the reason for refinement in the patient's clinical chart, per protocol (e.g., weekly TS assessments) or due to another reason.
5. Treatment protocol: Currently, two conventional protocols for stimulation of the L-DLPFC are approved and/or cleared by regulatory agencies for treatment of depression, and available in most TMS centers as acute/induction TMS treatment schedules, with sessions delivered daily over 20-30 daily sessions on weekdays¹¹
   1. High frequency rTMS: Deliver pulses with intensity at 120% of the rMT, and frequency of 10 Hz (3000 pulses per session, in sequential cycles of 4 s on and 26 s off, with a total duration of 37.5 min).
   2. iTBS: Deliver pulses with intensity at 120% rMT, in 50 Hz triplet bursts, repeated at 5 Hz (600 pulses per session, in sequential cycles of 2 s on and 8 s off, with a total duration of 3 min and 9 s).
6. During session: Ensure that the coil remains correctly located on the head over the TS throughout the session. If the patient experiences any discomfort, assist in normalizing the sensation and adjust the intensity if necessary. Session may be paused or discontinued at the patient's request.
7. Post-session procedures
   1. Instruct the patient to stand up slowly, while monitoring signs of dizziness or imbalance.
   2. Evaluate the presence of discomfort²³. For mitigation measures, suggest use over-the-counter analgesics or contact with the attending physician, in case of severe or persisting symptoms.

5. TMS treatment sessions (performed by TMS technician)

1. Pre-session check
   1. Ask the patient if they experienced any side effects from the previous session.
   2. Ask the patients for any changes in medication that might affect the rMT. Upon significant changes to medication, re-assess the rMT.
2. Hotspot confirmation
   1. Put the marked lycra cap back on the patient's head and check the MH to ensure the previously marked regions remain accurate.
   2. If adjustments are necessary, follow the procedures described for the first session to redefine the MH.
3. Treatment
   1. Place the coil at the TS and administer the stimulation according to the selected treatment protocol and the latest rMT assessment.
   2. Verify the position of the coil on the head of the patient during the session to ensure its accuracy.
4. Ramping: During initial treatment sessions, some patients experience scalp discomfort or muscle twitching that prevents immediate delivery of the full target stimulation intensity specified in the TMS protocol. In such cases, implement ramping to enhance patient comfort and tolerability. Ramping in TMS refers to the gradual increase of stimulation intensity over the first sessions, usually the first week of treatment (5 sessions).
   1. Instead of starting at the full prescribed intensity, begin stimulation at a lower percentage of the motor threshold (e.g., 100% rMT).
   2. Increases the stimulation intensity within session and/or across sessions, until the target intensity is reached, i.e., 120% of rMT.
      NOTE: This approach helps reduce initial discomfort, improve patient adherence, and minimize side effects such as scalp pain or headaches. Ramping is particularly beneficial for individuals new to TMS and those with heightened sensitivity to stimulation.
5. Post-session procedures: Follow the procedures outlined above (step 4.7).

6. Physician assessment (performed by prescribing physician)

NOTE: Depending on the physical and human resources available at each TMS center, medical appointments with the TMS physician are scheduled throughout the acute TMS treatment phase.

1. Assess patient's progress, address any side effects, and discuss potential mitigation strategies^17,23.
2. After the patient has completed 4 weeks of treatment, adjust the session frequency based on clinical response.
3. After the acute treatment phase, evaluate the patient's overall progress and discuss the next steps in treatment.
4. If clinically indicated, recommend transition to a maintenance phase according to center protocols and resources, and patient preference¹⁴.

Resultados

The efficacy of transcranial magnetic stimulation for the treatment of major depression episodes has been consistently confirmed in multiple meta-analyses, with response rates ranging from 40% to 70% and remission rates from 17% to 77%¹³. Consequently, its clinical and research applications have been expanding³³. However, significant variability in treatment outcomes persists¹³, possibly due to differences in protocols across TMS centers¹². Here, we provide a structured, step-by-step guide that promotes consistency across centers, towards enhancing clinical efficacy and patients' quality of life. Additionally, standardizing protocols facilitates more robust clinical data collection, contributing to research in real-world settings^24,27,34.

As an example, our TMS center routinely applies this standardized protocol and has contributed to a real-world evidence study evaluating the efficacy of TMS for depression²⁴. This study, which analyzed data from over 500 patients across several centers in multiple countries, compared treatment outcomes between older and younger adults²⁴. At the Champalimaud Foundation, the study was approved by the Champalimaud Ethics Committee, and informed consent was obtained from all participants. Between May 2019 and April 2021, 35 patients treated at our site met eligibility criteria for inclusion. For this study, in addition to eligibility for treatment with rTMS for TRD, participants were excluded if age or motor threshold data were missing, the treatment device was changed mid-course, fewer than 10 sessions were completed, or the average interval between sessions was ≥ 2.5 days. The mean age was 48.6 ± 16 years, and 51.4% were female. The most common indication for referral was unipolar depression (80%), with 20% of patients diagnosed with bipolar depression. The majority of patients (88.6%) received iTBS over the L-DLPFC. In cases where the left-sided protocol was not tolerated, a right-sided (R-DLPFC) low-frequency protocol used (11.4%). The rMT was assessed weekly, consistent with procedures from our previous research²⁷. The mean baseline rMT was 59.4 ± 14.0%, and the end-of-treatment rMT was 58.1 ± 16.8%. Most patients (80%) completed the full six-week acute treatment, with 8.6%, 2.9%, 5.7%, and 2.9% completing only five, four, three, and two weeks, respectively. No dropouts were attributed to protocol-related issues (e.g., coil discomfort, inability to reach target rMT), and non-completion resulted from dropout due to unspecified reasons. The clinical outcomes are illustrated in Figure 1. Mean MADRS reduction was 9.13 (± 9.82 SD), which was significantly different from zero (one-sample t-test, p < 0.001). Response and remission rates were not substantially different from previously reported evidence supporting the efficacy of TMS in the treatment of depressive disorders¹³. Regarding technician variability, we used a two-way mixed-effects model to calculate the intraclass correlation coefficient (ICC) for absolute agreement in rMT assessment between the first two weekly rMT measurements. Analyses were performed separately for measurements taken by the same technician (intra-rater) and by different technicians (inter-rater). Both ICC values indicated excellent reliability (ICC_Intra = 0.92, 95% CI 0.75-0.98, F_[11,11] = 23.79; p < 0.001; ICC_Inter = 0.88, 95% CI 0.75-0.95; F_[22,22] = 6.4; p < 0.001).

Regarding the results of the overall sample, while both age groups demonstrated similar overall antidepressant responses, older adults exhibited a delayed response compared to their younger counterparts²⁴. These findings suggest that extending the duration of TMS treatment may be necessary to achieve comparable therapeutic outcomes in older patients and aligns with previous research confirming the effectiveness of TMS in older populations, while highlighting the potential for age-specific adaptations in treatment protocols³⁵.

Integrating these findings into clinical practice requires careful consideration, as they directly support key aspects of the TMS protocol outlined in this work. Specifically, they emphasize the need for regular and extended monitoring of treatment progress, as well as the critical role of effectively managing patient concerns and expectations regarding the varying effects of TMS³⁶. Moreover, they highlight the importance of developing individualized treatment plans that incorporate comprehensive and routine assessments of multiple determinants, including socio-demographic factors (e.g., age), clinical variables (e.g., concomitant medication regimens), and treatment-related parameters (e.g., motor hotspot, motor threshold, and treatment site determination)¹⁷. These factors play a crucial role in optimizing both clinical efficacy and treatment tolerance⁶.

Figure 1: Antidepressant effect after 6 weeks of treatment. (A) Severity of depressive symptoms was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Mean MADRS reduction was 9.13 (± 9.82 SD), which was statistically significantly different from zero (one-sample t-test, p < 0.001). Error bars correspond to a 95% Confidence Interval. (B) A partial responder was defined as a patient who experiences at least a 25% reduction in the severity of depression, while a responder was considered if 50% or greater reduction of symptom severity was observed²⁴. Finally, remission was defined as a total score of MADRS ≤ 10^16,26. Clinical outcomes were similar to what has been previously reported¹³. Error bars correspond to a 95% Confidence Interval.Please click here to view a larger version of this figure.

Discussão

The implementation of a standardized TMS protocol in clinical settings ensures consistency in treatment delivery, optimizes patient outcomes, and enhances the reliability of therapeutic interventions for depression¹⁷. The protocol outlined in this study provides a structured framework for clinicians and technicians, addressing key procedural elements such as patient preparation, motor hotspot determination, and treatment site localization. By maintaining adherence to these steps, clinicians can reduce variability in treatment application^14,37,38, thereby potentially increasing the likelihood of achieving optimal clinical outcomes. Furthermore, integrating psychometric assessments at predefined intervals allows for systematic tracking of patient response, ensuring that treatment adjustments can be made based also on empirical data. In contrast to existing guidelines²³, this protocol specifies structured ramping strategies to optimize patient comfort during initial sessions and incorporates predefined psychometric assessment timelines to guide systematic, data-driven treatment adjustments.

Decision-making about the use of TMS to treat an episode of depression should be a collaborative decision between the patient and the prescribing clinician. In most circumstances, the clinician is a psychiatrist, already responsible for patient care, or to whom the patient was referred for assessment of the potential use of TMS. Indications with regulatory approval include TRD, with and without co-morbid anxiety, but also OCD and substance use disorders, with recent clearance of a protocol for smoking cessation¹¹. Protocols cleared by regulatory agencies for depression include high-frequency L-DLPFC stimulation^11,39. Off-label uses may be considered based on clinical evidence and expert guidelines. Additionally, promising data also support potential future use for other psychiatric syndromes, namely negative symptoms of schizophrenia and post-traumatic stress disorder, still lacking regulatory approval^11,12.

While the focus of this article is on a protocol for conventional rTMS, other protocols are also available. The selection of a specific TMS protocol should be guided by the attending physician, considering both patient and clinician preferences, the specific TMS device available, and the level of experience of the clinical staff. An accelerated TMS protocol (Stanford Neuromodulation Treatment) has been cleared by the FDA for treatment-resistant depression^11,16, but is not widely accessible in most TMS centers, despite being a very promising treatment strategy, namely regarding speed of onset^36,37. Other protocols, such as low-frequency rTMS targeting the R-DLPFC or bilateral stimulation involving both the L- and R-DLPFC, have demonstrated clinical efficacy^6,12. However, these approaches currently hold lower recommendation levels¹² and have not yet received regulatory clearance or approval¹¹. Low-frequency rTMS of the R-DLPFC, which may be required when high-frequency stimulation is not tolerated and/or the L-DLPFC is not accessible, is conducted with procedures for determining MH, rMT, and TS as described above, but adapted for the right hemisphere and left hand.

Ethical and regulatory issues should govern TMS use in clinical practice^17,18. A fundamental requirement is obtaining informed consent, which must be free and prior to treatment, based on providing all relevant information about procedures, potential risks, and discomforts in an understandable way^17,18. Informed consent should clearly discuss the possibility of the occurrence of side effects, particularly a seizure, and clinicians must ensure patients understand the information provided^17,18. Full disclosure of the treatment plan, including whether off-label protocols are used, is critical in the informed consent process^17,18. Safety is another critical consideration^17,18. While generally safe and well-tolerated, the most serious acute adverse effect is the occurrence of a seizure, which is extremely rare when treatment is delivered within recommended parameters^11,17,18. Certain conditions and medications can increase the risk of seizures, such as a personal history of epilepsy, brain lesions, administration of drugs lowering seizure threshold, sleep deprivation, and alcoholism¹⁸. Other adverse effects, mostly mild and self-limited, can include scalp pain, headache, muscle twitching, dizziness, nausea, anxiety, insomnia, hypomania, and tinnitus^11,17,18,39. Absolute contraindications include the presence of metallic hardware in close contact with the coil, such as cochlear implants or implanted pulse generators, due to the risk of inducing device malfunction¹⁸. Other conditions, like pregnancy or severe heart disease, involve increased or uncertain risk¹⁸.

Patient comfort and adherence^40,41,42 play crucial roles in treatment success⁴³. The protocol includes specific measures to improve tolerability, such as initial familiarization with TMS sensations, the use of earplugs to enhance auditory safety, and the implementation of ramping strategies to gradually increase stimulation intensity. These adaptations are particularly valuable for individuals who experience discomfort during early sessions, potentially improving patient retention and overall treatment effectiveness⁴³. The inclusion of structured post-session evaluations also enables the early detection and management of side effects, reinforcing patient safety and engagement throughout the treatment course⁴³.

In addition to TMS equipment with local regulatory approval or clearance (e.g., CE mark in the EU, FDA in the US), sites where rTMS is delivered should be equipped with appropriate life-support equipment, and access to emergency medical facilities is also advised in medical environments where outpatient TMS treatments are delivered¹⁸. TMS clinics must have an explicit plan to address syncope and seizures, and every member of the TMS team must be familiar with it¹⁸. For suspected syncope, lying the patient down in a supine position with legs elevated is appropriate¹⁸. In case of seizures, efforts should focus on preventing complications like aspiration, turning the patient on one side (left lateral decubitus position is desirable) once movement ceases¹⁸. TMS-induced seizures are typically brief and self-limited, delayed recovery of consciousness beyond 30 s warrants further medical evaluation¹⁸. While life-support equipment should be available in TMS clinical centers¹⁸ for outpatient clinical settings applying standard protocols, the consensus of the Clinical TMS Society is that intravenous access, cardiac defibrillators, suction, and oxygen are not necessary¹⁷.

Appropriate training for personnel is a crucial step in setting up a TMS clinic¹⁹. The required credentials and training depend on the site and the local regulatory requirements, as well as the type and purpose of the TMS application^17,18,19. At our center, this includes completion of a certified TMS training program and supervised performance of TMS. Trainees should demonstrate proficiency in MH localization and rMT determination, accurate coil positioning, and adherence to safety procedures, before independent operation. Periodic re-assessment and refresher training are also recommended to maintain standardization. Particularly when rTMS is used as treatment for a medical condition, a licensed physician, serving as the medically responsible clinician, supervises application of treatments, which can be carried out by a trained medical assistant^17,18,19. TMS technicians, especially those without medical training, should have basic knowledge of brain physiology, TMS mechanisms, potential risks, and physiological changes induced by treatment^17,18,19. It is also recommended that TMS technicians have cardiopulmonary or basic life support training^17,18. Additionally, personnel skilled in the management of syncope and seizure should be present in TMS clinics^17,18. Finally, for routine clinical treatment sessions, a physician should be accessible in case of an emergency^17,18.

Another critical component of effective TMS administration is the precise determination of the stimulation site¹⁷. Here, we highlight the importance of using structured non-neuronavigated approaches such as the 5 cm rule and the Beam F3 method to identify the L-DLPFC as the primary target for depression treatment^44,45. While non-neuronavigated methods are practical, they nevertheless have limitations such as inherent inter-individual anatomical variation, with implications for precision, accuracy, and reproducibility^45,46,47,48. On the other hand, while neuronavigation offers the highest accuracy⁴⁹, limited availability in clinical settings may limit access if other methods are not used¹⁷. Moreover, neuronavigation did not offer a consistent clinical advantage when compared to non-neuronavigated methods⁵⁰. The step-by-step protocol presented here provides detailed guidance on the latter approaches, ensuring that even without neuronavigation, treatment sites can be determined consistently and reliably²⁷. Future research should explore how progress in imaging technology and real-time neuronavigation could further enhance the precision and efficacy of TMS interventions.

The structured assessment sessions incorporated into the protocol provide an evidence-based approach to monitor treatment efficacy and patient response. Regular psychometric assessment using standardized instruments such as the BDI-II and MADRS allows clinicians to track improvements and determine whether modifications to the treatment plan are necessary^24,27. Moreover, periodic reassessments of the rMT ensure that stimulation parameters remain optimal, accounting for any physiological changes that may occur over the course of treatment^27,51. While this is expected to contribute significantly to the safety of rTMS, recent evidence indicates that neither motor threshold and its stability, nor treatment intensity, reliably predict clinical outcomes^27,52. Finally, baseline assessments, such as the YMRS, may be used to identify patients at risk of mania, hypomania, or mixed states⁵⁰. In such cases, treatment adjustments may include closer clinical monitoring and coordination with the prescribing physician, medication adjustments (e.g., optimizing mood stabilizers) to mitigate the risk of mood switching, and consideration of the need to postpone rTMS treatment⁵⁰. This systematic approach underscores the importance of objective, data-driven decision-making in TMS therapy.

Depending on the resources and protocols of each TMS center, as well as patient preference, treatment may transition to a maintenance phase TMS protocol if this is considered of clinical interest¹⁴. This decision is typically based on clinical response to TMS and risk of relapse, and follows a pre-defined schedule (e.g., weekly, or biweekly sessions) that can be adjusted according to ongoing psychiatric evaluation. While no standardized protocol exists for transitioning to maintenance, a gradual reduction in session frequency is commonly employed (e.g., three sessions per week, then two sessions per week, and finally weekly) until the target maintenance schedule (e.g., biweekly) is reached^14,30. Symptom prompted maintenance protocols have also been described, where short cycles of rescue TMS session are applied when symptoms relapse^14,30. Currently, there is no evidence to support a given type of maintenance strategy over another^14,30.

Even with a structured protocol, challenges may occur during rTMS administration. Difficulty eliciting or locating the motor hotspot can often be addressed by verifying coil orientation and contact, exploring adjacent scalp positions, increasing intensity in small steps, and ensuring that the patient is relaxed^17,18,36. If a patient does not tolerate stimulation, strategies include ramping intensity over initial sessions, slightly adjusting coil placement, or using over-the-counter analgesics^17,18,36. In case of session interruptions due to equipment issues, patient discomfort, or unforeseen events, the session should be paused, the problem resolved, and stimulation resumed only once correct coil positioning and patient readiness are re-confirmed. Coil instability can be minimized with proper head and neck support, consistent cap alignment, and coil-holding devices^17,18. Variability in motor threshold measurements should prompt reassessment and review of technique and equipment if changes are abrupt^17,18,24,36. Auditory discomfort is best prevented with well-fitted, regularly replaced earplugs^17,18. Applying these measures improves comfort, accuracy, and treatment consistency.

While our goal is to offer practical guidance for the clinical use of TMS in depression, several limitations merit note. First, we rely on non-neuronavigated scalp targeting (5 cm rule, Beam F3). These methods are accessible and standardized but depend on individual anatomy and can reduce placement precision. Neuronavigation may improve coil-placement accuracy, but it is not universally available and has not shown a consistent clinical advantage in treatment outcomes. Second, while rMT-based dosing is essential for safety and standardization, it does not reliably predict antidepressant efficacy. Nevertheless, to date, no alternative dosing approach has shown sufficiently consistent results to replace rMT as the dosing anchor. Finally, we present maintenance treatment as optional because schedules vary across centers and no single strategy has proven superior. Future work should define more specific, evidence-based maintenance schedules.

In conclusion, the protocol outlined in this study provides a comprehensive, step-by-step framework for application of rTMS in the treatment of depression, balancing standardization with individualized care. Variability in clinical outcomes is addressed through the use of consistent targeting methods, clear stimulation parameter definitions, and structured procedural steps, while still allowing flexibility for patient-specific adjustments. In resource-rich settings, integration of neuronavigation and targeting based on functional imaging may further enhance precision and reproducibility. Future studies should focus on optimizing stimulation parameters, refining targeting strategies, and evaluating the long-term efficacy of structured TMS protocols, including the role of maintenance sessions and personalized adjustments in sustaining therapeutic benefits beyond the acute phase.

Materiais

Lista de materiais utilizados neste artigo

Nome	Empresa	Número de catálogo	Comentários
BA9 BA8 BA43 Location System	Will Beam & Jeff Borckardt	Web Interface Developed 6/7/2010	https://clinicalresearcher.org/F3/
Computer Desktop/Laptop	Irrelavant	Not applicable	Required to access BeamF3 website
Confortable Chair	Irrelavant	Not applicable	For the patient to seat while all TMS procedures are performed
Cool-B65 Coil	Magventure	9016E0491	TMS coil
Microsoft Excel	Microsoft	Office 365 Personal	Useful to store TMS patients clinical data
Paper	Irrelevant	Not applicable	Required to print the psychometric instruments and the score sheets
Pen	Irrelevant	Not applicable	Required to complete the psychometric instruments
Printer	Irrelevant	Not applicable	Required to print the psychometric instruments and the score sheets
Transcranial Magnetic Stimulation (TMS) MagPro X100	Magventure	9016D0041	TMS operaring system