Patterned repetitive transcranial magnetic stimulation (rTMS) protocols like Theta Burst Stimulation (TBS) and Quadri-Pulse Stimulation (QPS) have revolutionized the field of non-invasive brain stimulation by providing powerful, precise tools to modulate brain plasticity. These protocols induce lasting changes in cortico-spinal excitability in human motor cortex (M1) that resemble long-term potentiation (LTP)-like facilitation and long-term depression (LTD)-like inhibition, which are key mechanisms underlying learning, memory, and recovery after injury.

This article provides a comprehensive overview of these protocols, their pulse structures, total dose considerations, cortical circuits and oscillations involved, and their clinical and research significance.

Patterned rTMS: Why Patterning Matters

Unlike traditional rTMS that delivers pulses at regular intervals, patterned rTMS delivers pulses grouped in bursts designed to mimic endogenous neural rhythms or optimize intracellular processes like calcium influx. This temporal patterning enhances the ability to induce stronger, more consistent plastic changes in targeted brain areas.

Theta Burst Stimulation (TBS)

What Is TBS?

• Pulse Structure: Bursts of 3 pulses at 50 Hz (each pulse separated by 20 ms), repeated at 5 Hz (one burst every 200 ms).

• Protocols:

  • Intermittent TBS (iTBS): Bursts given intermittently, which facilitate cortical excitability (LTP-like effect).

  • Continuous TBS (cTBS): Bursts delivered continuously, which inhibit cortical excitability (LTD-like effect).

• Duration and Dose:

  • Typically applied for 40 seconds to 3 minutes.

  • Total pulse counts range around 600 pulses per session.

Mechanisms and Circuitry

• Mimics the brain’s natural theta rhythm (~5 Hz), notably present in hippocampus and cortex, linked with enhanced plasticity.

• Primarily activates excitatory and inhibitory interneuronal circuits in M1 responsible for modulating motor output.

• Plasticity induced by TBS depends on burst timing and synaptic calcium dynamics.

Clinical and Research Use

• Used extensively in research to study plasticity and in therapy for depression, stroke rehabilitation, and neuropsychiatric diseases.

• Advantages include short duration and strong physiological effects without discomfort.

Quadri-Pulse Stimulation (QPS)

What Is QPS?

• Pulse Structure: Bursts consisting of 4 monophasic pulses delivered in rapid succession from independent stimulators.

• Critical Parameter: Inter-pulse interval (IPI) within a burst:

  • 5 ms IPI (“QPS-5ms”): Produces excitatory/facilitatory (LTP-like) effects.

  • 50 ms IPI (“QPS-50ms”): Produces inhibitory (LTD-like) effects.

• Inter-Burst Interval (IBI): Typically 5 seconds between bursts, optimizing sustained aftereffects.

• Total Dose: Approximately 1,440 pulses per session, delivered in 360 bursts.

Mechanisms and Circuitry

• Uses monophasic pulses that produce more substantial and longer-lasting aftereffects than biphasic pulses.

• Activates multiple cortical populations with greater precision, resulting in less variability of responses between individuals.

• Exhibits consistent bidirectional modulation with strong reliability; 80% of young adults respond robustly.

Innovations and Clinical Implications

• New stimulators like DuoMAG MP-Quad enhance practical application.

• Potential clinical use for motor rehabilitation and neurological disorders is being actively explored.

Total Dose, Circuits, and Oscillations in Patterned rTMS: Insights from qTBS

A novel protocol merges TBS and QPS into quadri-pulse theta burst stimulation (qTBS) to leverage benefits of both.

Total Dose and Stimulation Parameters

• 360 bursts each with 4 pulses = 1,440 pulses delivered at 90% active motor threshold.

• Bursts repeated at 5 Hz (theta rhythm).

• Internal burst frequencies tested:

  • 666 Hz (1.5 ms pulse interval): Matches natural I-wave periodicity of cortico-spinal volleys.

  • 200 Hz (5 ms pulse interval): Maximizes postsynaptic calcium influx, independent of I-wave timing.

Cortical Circuits and Oscillations

• TMS excites complex cortical microcircuits generating I-waves — high frequency (~600-670 Hz) oscillations caused by synchronized activation in pyramidal neurons and interneurons.

• Induced current direction matters:

  • Posterior-Anterior (PA) current tends to activate early I-waves.

  • Anterior-Posterior (AP) current engages later I-waves.

• These differences in circuit recruitment govern plasticity outcomes.

Plasticity Findings

• At 666 Hz, qTBS induces direction-dependent plasticity:

  • PA current leads to inhibition (LTD-like).

  • AP current leads to facilitation (LTP-like).

• At 200 Hz, both PA and AP produce strong facilitation, likely due to enhanced calcium influx overriding timing specificity.

• Effects last for at least 60 minutes post-stimulation.

Summary Comparison of TBS and QPS

Clinical and Research Perspectives

• TBS offers rapid, effective modulation and is widely applied, especially in psychiatry.

• QPS provides greater control, reliability, and sustained plasticity, positioning it as a promising candidate for therapeutic brain stimulation.

• The combined qTBS approach leverages rhythmicity and burst precision to refine therapy, tailoring effects by current direction and burst frequency.

• Understanding cortical oscillations and microcircuits enables clinicians and researchers to utilize patterned rTMS to target specific pathways for rehabilitation and psychiatric treatment.

Conclusion

Patterned rTMS protocols like Theta Burst Stimulation and Quadri-Pulse Stimulation enhance our ability to non-invasively modulate human brain plasticity with precision and reliability. The interplay of pulse timing, dose, cortical circuit oscillations, and induced current direction shape the nature, direction, and durability of plastic changes generated. Continued innovation and research in these techniques hold transformative potential for neuropsychiatric and neurological therapies.