Meta-analysis on paired associative and theta burst stimulation

If TMS is applied in a repeated fashion for 15-30 minutes, effects can be observed for more than an hour after stimulation. Repeated TMS (rTMS) is therefore used in therapeutic settings in the treatment of psychiatric and neurological disease (read more in the Brain Stimulation Therapy section). In an attempt to further develop the method, other exclusive rTMS-like paradigms have been developed. Two examples of such special rTMS methods are paired associative stimulation (PAS) and theta burst stimulation (TBS). In two meta-analysis we summarized studies using this techniques to determine whether the are effective in increasing activity of the brain. 

PAS is an rTMS technique that specifically can increase activity in the motor cortex. A TMS pulse is applied over the motor cortex that is connected to a specific muscle. Shortly before an electric pulse is given to the muscle. The idea is that there are two signals simultaneously in the motor cortex: 1. the activity from the TMS pulse, and 2. the activity from the muscle that traveled back to the motor cortex. This coming together of two signals promotes strengthening the connection of neurons. However, if the timing is not on point, the motor cortex can become less activated. Since PAS relies on stimulation of the muscle, this technique only works in the motor cortex.

TBS is another rTMS technique. This one applies TMS in a very specific rhythm, very fast rhythm. Three pulses within 50 millisecond, which is repeated every 200 milliseconds. This is repeated for either repeated in 2 second chunks with breaks in between, or in one continuous stream of 40 seconds. The protocol with pauses is thought to increase activity in the brain. The continuous stream is thought to 'fatigue' the brain resulting in lower activity. This technique can be applied over the entire brain, but for this meta-analysis we looked at activity over the motor cortex.

Paired associative stimulation
Theta burst stimulation

Results and discussion

Results of PAS meta-analysis (left picture) confirmed the hypothesis. Simultaneous signal PAS led to an increase in activity. These effects are stable for 60 minutes afster stimulation, after which they reduce. After two hourse the effect is gone. PAS with signals that are not simulatenous leads to decreased activity in motor cortex. This effect is strongest immediatelly after stimulation and gradually reduces over time. But, even after two hours a significant reduction in activity can be seen.

The results of the TBS meta-analysis (right picture) also confirmed the hypothesis. TBS with breaks increases brain activity. This effect peaks 15 minutes after stimulation after which it gradually reduces. In total the effect remains for 60 minutes. Continuous TBS decreases brain activity.  The effect gradually disappears over time and lasts for 50 minutes.

Overall, our analyses showed that both PAS and TBS can reliable increase or decrease brain activity with effects roughly between 1 and 2 hours. It should be noted that this effect is observed after one application. When stimulation is applied over multiple days or even weeks, effects can be much more long lasting.


Wischnewski & Schutter (2016). Efficacy and time course of paired associative stimulation in cortical plasticity: Implications for neuropsychiatry. Clin Neurophysiol, 127(1), 732-739.

Wischnewski & Schutter (2015). Efficacy and time course of theta burst stimulation in healthy humans. Brain Stimul, 8(4), 685-692.