Transcranial Magnetic Stimulation Effects on Cognitive Control of Emotion: A Gradual and Subtle Paradigm Shift.

I n this issue of JECT, Lantrip et al 1 discuss the hypothesis that transcranial magnetic stimulation (TMS) derives its antidepressant actions via a fundamental enhancement of the cognitive control network (CCN). This view draws on 2 theoretical constructs and their associated lines of evidence. First, that depression is fundamentally a disorder of cognition. Though not new, this perspective has emerged as a significant refinement of the classical view of the tripartite mind (thinking/emotion/will). This model asserts that the cognitive deficits associated with depression represent more than mere epiphenomena. Rather, they are central to understanding the interplay between dysfunctional brain regions subserving emotional processing. The second line of evidence pertains to the putative effects of TMS on neural and, by degrees, cognitive function locally in the cortical region being stimulated and in a distributed way as pathways of structural and functional connectivity dictate. The nature of this neuromodulation, as well as its variability and durability across patient populations and with different stimulus characteristics, is a subject of intense study. Although there is clear evidence for antidepressant effects of TMS, response and remission rates are modest and diminish significantly with advancing degrees of medication treatment resistance. From this perspective, TMS still has much to prove to the JECT readers who have collectively borne witness to the rapid and robust effects of ECT. However, those of us who perform both procedures have begun to see that there may be a unique potential for TMS despite the apparently gradual and subtle manner in which it manifests clinical improvement. In a recent case series, we demonstrated similar response and remission rates between patients receiving ECT versus those treated with TMS, although the latter group required 2 to 3 times as many treatments and a correspondingly longer course of treatment. There are a number of implications emerging from this expectation, not the least of which is that the cognitive mechanisms of our treatments matter greatly and, as a corollary, we need to develop biomarkers or at least more precise methods to monitor changing patterns of cognition with treatment to ensure that the gradual and subtle changes are proceeding in the expected direction. For instance, Beynel at al have demonstrated enhanced performance in the antisaccade inhibition task in depressed patients treated with a course of intermittent thetaburst (excitatory) stimulation of the dorsolateral prefrontal cortex (DLPFC) in depressed patients with bipolar disorder, correlating with improvement in mood symptoms. The central postulate that TMS effects on depression are mediated by changes in the CCN has implications for other psychiatric illnesses similarly characterized by cognitive impairments and emotion abnormalities. Of interest, schizophrenia spectrum disorders are marked by cognitive impairments (their performance is often 1.5 to 2 SDs lower than control samples) at all illness stages contributing to poor psychosocial functioning. Much like major depressive disorder (MDD), patients with schizophrenia demonstrate reduced working memory, cognitive inhibition, flexibility, and error monitoring—all indicative of impaired cognitive control. Moreover, the characteristic uses of suppression as an emotion regulation strategy and inability to use reappraisal to regulate negative emotion states are prevalent in schizophrenia. A few studies have now examined the benefits of TMS on cognition in schizophrenia. Some suggest that high-frequency (at least 10 Hz) TMS targeted bilaterally to the DLPFC may improve activity in the DLPFC, working memory, verbal memory, and facial emotion perception. Dosing in patients with schizophrenia exceed those seen in studies of MDD, with stimulation provided once or twice daily for as many as 30 sessions. Questions remain regarding the necessary dosage and configuration of TMS needed to increase activity in the CCN and improve cognitive functions in a robust manner. Furthermore, studies would need to establish that cognitive benefits are associated with improved