Reply to: Deep Brain Stimulation for Depression: Is It a Gray or White “Matter”?

Correspondence Reply to: Deep Brain Stimulation for Depression: Is It a Gray or White “Matter”? To the Editor: We thank Etiévant et al. (1) for their comments and the opportunity to discuss our data. In response, we should first consider some of the concepts involving deep brain stimulation (DBS) at high frequencies (e.g., .100 Hz). One of the mechanisms commonly described is a depolarization block. This mechanism is characterized by a state in which cells undergo depolarization with an almost complete abolishment of spontaneous action potentials (functional inactivation) (2). In addition, DBS excites fiber pathways in the vicinity of the electrodes (efferent and afferent projections from and to the targeted region as well as fibers en passant) (2,3); this is important, as the anterograde and retrograde propagation of action potentials may influence the functioning of brain regions projecting to or receiving projections from the stimulated site. Finally, DBS has been shown to modulate activity of glial cells and induce plastic changes, such as long-term potentiation, increases in neurotrophin levels, and neurogenesis (3–6). In contrast to the complexity of the above-described mechanisms, optogenetics, which is often delivered for short periods of time at much lower frequencies, is a very clean technique that allows the precise distinction of the neural elements involved in mechanisms of behavioral and physiologic processes. Since our initial study (7) and in a further appraisal of our data (6), we have noted that the stimulation of fibers was an important mechanism for the antidepressant-like effects of prefrontal cortex (PFC) DBS. This conclusion was reached based on a series of results that showed that DBS was not only effective in animals that had ibotenic acid (IBO) PFC lesions, but also able to induce serotonin release (7), and increase neurotrophin levels in structures at a distance from the target (5). In our 2010 study, the modulation of prefrontalraphe projections was one of the proposed mechanisms for a stimulation-induced serotonin release (7). The hypothesis that DBS modulates PFC fiber projections is not incongruent with experiments showing that optogenetic excitation of PFC neurons induces antidepressant-like effects in rodents (8). Despite differences in firing rate and pattern, both may lead to the activation of structures at a distance from the target. In regard to ablative/inactivation processes, we reported that PFC radiofrequency lesions or muscimol injections were associated with some degree of antidepressant-like response in the forced swim test (7). However, this response was of much lower magnitude than the effects obtained with DBS. We have not tested the effects of radiofrequency lesions or muscimol injections combined with DBS, as erroneously stated in the letter by Etiévant et al. Both our groups found that PFC IBO alone did not reduce immobility in the forced swim test. Differences in results refer to experiments applying DBS into IBO-lesioned sites. Although we showed unaltered stimulationinduced antidepressant-like responses (7), Etiévant et al. have found DBS to be largely ineffective. The suggested possibility that we did not damage cells by using a lower dose of IBO

Biological Psychiatry

seems unlikely, as injection sites in our study were clearly gliotic and devoid of neurons (7). However, as noted by Etiévant et al., it is possible that the higher doses of IBO in their study may have caused more pronounced damage. Even at a concentration twice as high as the one in our study, axonal projections from cortical neurons have been shown to be viable 2 months after cell bodies were injured by IBO (9). Thus, it is conceivable that the doses of IBO used in our study may have largely compromised cell bodies without fully affecting axonal projections. We suggest that by using higher doses of IBO, Etiévant et al. may have injured PFC neurons as well as their axons, rendering DBS ineffective. Although this explanation would help to reconcile discrepancies between our studies, it is speculative and would need to be verified in further experiments. Clement Hamani José N. Nobrega

Acknowledgments and Disclosures This work was supported in part by the Ontario Mental Health Foundation and Canadian Institutes of Health Research. The authors report no biomedical financial interests or potential conflicts of interest.

Article Information From the Neuroimaging Research Section (CH, JNN), Centre for Addiction and Mental Health, University of Toronto; and Division of Neurosurgery (CH), Toronto Western Hospital, Toronto, Ontario, Canada. Address correspondence to Clement Hamani, M.D., Ph.D., Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; E-mail: [email protected]. See also associated correspondence: http://dx.doi.org/10.1016/j.biop sych.2015.11.029.

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Etiévant A, Lucas G, Haddjeri N (2016): Deep brain stimulation for depression: Is it a gray or white “Matter”? Biol Psychiatry [published online ahead of print]. Florence G, Sameshima K, Fonoff ET, Hamani C (2015): Deep brain stimulation: More complex than the inhibition of cells and excitation of fibers [published online ahead of print Jul 6]. Neuroscientist. Hamani C, Temel Y (2012): Deep brain stimulation for psychiatric disease: Contributions and validity of animal models. Sci Transl Med 4:142rv148. Bambico FR, Bregman T, Diwan M, Li J, Darvish-Ghane S, Li Z, et al. (2015): Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats. Transl Psychiatry 5:e674. Hamani C, Machado DC, Hipolide DC, Dubiela FP, Suchecki D, Macedo CE, et al. (2012): Deep brain stimulation reverses anhedoniclike behavior in a chronic model of depression: Role of serotonin and brain derived neurotrophic factor. Biol Psychiatry 71:30–35. Hamani C, Nobrega JN (2012): Preclinical studies modeling deep brain stimulation for depression. Biol Psychiatry 72:916–923. Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, GonzalezLima F, et al. (2010): Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 67:117–124. Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, et al. (2010): Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 30:16082–16090. Fowler GA, Sherk H (2001): Prolonged survival of axons terminating within lesions of cat visual cortex. Neurosci Lett 311:66–68.

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