Feasibility of simultaneous cognitive behavioral therapy and left prefrontal rTMS for treatment resistant depression

Abstract

Daily left prefrontal rTMS has emerged as a potentially useful treatment for acute major depression(1-3) and is now United Stated FDA approved. TMS was initially developed as a treatment based on the theory that in depression the prefrontal cortex was deficient in many tasks, including governing limbic activity (4). Repeated subconvulsive stimulation of the prefrontal cortex was theorized to reset the normal cortico-limbic regulatory circuit (5). Recent animal work supports this notion. Maier and colleagues (6) have studied the neurobiological basis of learned helplessness and resilience to repeated stressors (7-8). In this model of depression or PTSD, the animal with control over a stressor does not develop learned helplessness while being shocked, while the animal without control does. Both animals receive the same stress. Thus the ‘concept’ of being in control prevents the animal from developing learned helplessness. In a series of recent studies, Maier and colleagues have recently shown that the ‘concept of control’ is actually a signal from the prefrontal cortex to the dorsal raphe nucleus (7). Lesioning this circuit makes an animal who actually has behavioral control over a stressor still develop learned helplessness. Stimulating this circuit even while not providing a control lever protects from learned helplessness (8). They thus conclude that ‘the concept of control is a regulatory circuit from the prefrontal cortex to the dorsal raphe nucleus (DRN). These animal findings suggest that cortico-limbic and cortico-brainstem regulation during exposure to stress depends on a previously learned “sense of control” and that prefrontal stimulation during acute uncontrollable stress may “mimic” that learned experience and is protective against developing depression and, possibly, PTSD. Interestingly, most therapeutic TMS studies have not dictated what patients should do or think about while receiving therapy, other than to not fall asleep. This glaring omission is even more concerning as there is ample evidence with TMS that plasticity in the brain in response to stimulation depends on the state of the brain or the activation of the circuit during stimulation(14). Numerous studies in single cell recordings or circuit behavior have confirmed that a circuit is more ‘plastic’ or able to change its firing efficiency, if the circuit is active during stimulation. Hebb's rule postulated that cells that fire together, wire together. That is, their synaptic efficiency increases over time with conjoint firing (9). Cognitive behavioral therapy (CBT) was originally developed based on the cognitive model of depression. However, it became clear that the cognitive predisposition to depression may be related to the impact of stress on neural functioning (10). There is increasing evidence that psychotherapy (11) and CBT in particular (12) affect brain function and even brain structure (13). At the same time, the effect of CBT on the function of prefrontal areas of the brain needs further study (11). If the animal data on the ‘perception of control’, provided by the stimulation of prefrontal cortex are correct, TMS stimulation of the left prefrontal cortex might synergistically reinforce the activity of CBT, bringing the regulatory circuit back on line faster and with more resilience. However, there are practical issues involved in administering CBT to a patient in the TMS chair. We wondered whether one could actually perform CBT in the TMS chair, while a patient is receiving left prefrontal rTMS for treating depression. The present report demonstrates that it is feasible to perform modified CBT during TMS of the left prefrontal area in a depressed patient.