The results of the current study suggest that the left frontal fast-frequency rTMS administered over 20 days is associated with improvements in some cognitive functions and reduction in depression severity in a pilot sample of treatment-resistant depression patients. Specifically, the concept-shifting ability, measured as accuracy of performance on the mCST, has improved on the last 10 days after the rTMS compared to the first 10 days before the rTMS in patients (Table 2). This improvement in patients was statistically significant and with a high effect size (.78) in contrast to the same comparison which was not significant and had a small effect size (.18) in healthy volunteers. Therefore, it can be speculated that the improvement in the task accuracy in patients was not due to practice alone following a multiple completion of the same task over 20 days because the same improvement was not observed in healthy volunteers. In contrast, all other cognitive improvements on the accuracy and duration of performance on the mCST were similar in both groups (patients and healthy volunteers) in terms of statistical significance and effect sizes and thus could not be specifically attributed to the rTMS.
In addition to improvement in the concept-shifting ability, an improvement in the immediate memory was seen after 20 days of rTMS compared to baseline in patients (Table 3). This result is in line with the improvement on a list-recall test following two weeks of a fast rTMS to the left DLPFC in patients with major depression . The preliminary evidence from both studies suggests that the rTMS might be superior (or at least not worse) compared to the ECT in terms of not having the detrimental effects on memory that are seen after the ECT . However, in general, it appears that the positive effects of rTMS on the cognitive functioning depend on the paradigms studied and the parameters of rTMS used and thus are not always observed .
In the current study it is unlikely that the performance on the mCST improved as a direct result of an improvement on the immediate memory since the scores on both tasks did not correlate. Instead of a cause-effect relationship, the improvement in both cognitive functions might be due to the direct or indirect (trans-synaptic) alteration of the DLPFC functioning. Specifically, the effect on memory, which is controlled by the left temporal cortex, suggests that the rTMS likely activates neural areas beyond the stimulation site either directly or indirectly by first activating the DLPFC which might have connections to these sites . For instance, if the fast-frequency rTMS is mainly excitatory  it could reverse the reduced medial/middle prefrontal and hippocampal activity that are related to the positive affect in treatment-resistant depression . On the other hand, if the fast-frequency rTMS has inhibitory properties  then it could reduce the temporal lobe hyperactivity that appears to be related to the negative affect disturbances in treatment-resistant depression . The fast-frequency rTMS could also have transient effects, such as an increase in the neural activity during stimulation followed by hypoactivity . In general, the changes in neural activity induced by the fast-frequency rTMS could result from increases in blood flow in regions implicated in depression, such as bilateral frontal, limbic and paralimbic regions , activation of the hypo-thalamo-pituitary axis indirectly measured by increases in serum thyroid-stimulating hormone, TSH , and/or stimulation of the prefrontal glutamatergic neurons at the stimulation site (left DLPFC) and also in remote brain regions, such as right DLPFC and left cingulated cortex .
The improvement in the cognitive functioning was accompanied by a reduction in severity of depression symptoms after the last rTMS compared to baseline in patients confirming the antidepressive properties of the left frontal high-frequency rTMS found in other studies . It is difficult to speculate about the mechanism of reduction in depression symptoms following the rTMS based on the current data. One possibility could be that the rTMS alleviates depression and as a consequence improves cognitive functioning but the opposite could also hold true. On the other hand, the rTMS may independently alter both the cognitive ability and depression symptoms, perhaps by activating different neural pathways and regions. The last explanation appears possible since there were no significant correlations between cognitive functioning and depression scores in the current study.
One limitation of the current study is a lack of a matched clinical group and a matched healthy control group. Ideally, the current study should be expanded to test the performance on the mCST in patients receiving sham stimulation. However, the use of sham treatment in the rTMS is questionable because it appears that patients are able to correctly guess if they receive a real or a sham treatment based on their mood improvements experienced during the real rTMS . It can be speculated that since not all cognitive functions improved following 20 days of the rTMS it is unlikely that the results in patients were due to placebo effect alone.
Another difficulty with the interpretation of results, seen not only in the current study but rather in most rTMS studies of treatment-resistant depression , is that the rTMS was used as an add-on treatment to a stable medication. Thus, the current improvement in cognitive functioning and reduction in severity of depression symptoms could be due to the combination of pharmacological treatment and the rTMS rather than the rTMS alone (assuming that placebo and/or practice effects were fully eliminated). In general, studies on patients receiving the rTMS monotherapy show the highest antidepressive properties (highest effect sizes) compared to studies using the rTMS as an add-on treatment . Further studies on medication-free patients are needed to investigate the effects of the rTMS as a mono-therapy on various cognitive functions. Even though potentially confounding, a concurrent pharmacological treatment might be necessary to maintain the antidepressive effects of rTMS after cessation of rTMS .
Furthermore, the clinical significance of the improvements in the concept-shifting ability and the immediate memory were not investigated in the current study. In general, the prevalence of depression is high (approximately 11-15%) worldwide  and depression is associated with a high burden and social disability. It can only be speculated that the improvements in cognitive functioning associated with the rTMS contributed to at least some improvement in the well-being of the current patients. Since there was no follow-up, it is also unknown if the reduction in severity of symptoms and the improvements in cognitive functioning would persist and for how long following cessation of the rTMS treatment. In general, it appears that 1–4 weeks of the rTMS is well-tolerated but it is unclear if the therapeutic effects of treatment persist over time and if so, for how long .