Brain PET metabolic substrate of TMS response in pharmaco-resistant depression

Over the past decade, repetitive transcranial magnetic stimulation (rTMS) has been increasingly developed in treatment-resistant depression (TRD). Several coils, parameters and stimulation targets have been proposed. Nevertheless, rTMS remains effective for only 30–40% of patients suffering from TRD [[1]Gellersen H.M. Kedzior K.K. Antidepressant outcomes of high-frequency repetitive transcranial magnetic stimulation (rTMS) with F8-coil and deep transcranial magnetic stimulation (DTMS) with H1-coil in major depression: a systematic review and meta-analysis.BMC Psychiatr. 2019; 19: 139https://doi.org/10.1186/s12888-019-2106-7Crossref PubMed Scopus (14) Google Scholar]. Individual-level predictors of response to rTMS therapy could improve these moderate results by guiding the selection of patients, and proposing more adaptative stimulation protocols. Towards this aim, several biomarkers are currently being evaluated, and neuroimaging markers seem easier to define and more reproducible [[2]Kar S.K. Predictors of response to repetitive transcranial magnetic stimulation in depression: a review of recent updates.Clin Psychopharmacol Neurosci. 2019; 17: 25https://doi.org/10.9758/cpn.2019.17.1.25Crossref PubMed Scopus (46) Google Scholar]. The objective of this report is to identify the regions of brain metabolism that evolve after rTMS therapy with symptomatic responses, and to secondarily search for predictive metabolic features. Our data were derived from a prospective controlled trial (NCT02559466). Forty-five patients suffering from TRD were initially randomized to receive either 20 sessions of conventional rTMS (n = 23) or double cone rTMS (n = 22), and nine patients discontinued. Statistical analyses completed with the intention-to-treat approach did not show any differences in clinical scores between the standard rTMS group and the deep-rTMS group [[3]Tastevin M. Baumstarck K. Groppi F. Cermolacce M. Lagrange G. Lançon C. et al.Double cone coil rTMS efficacy for treatment-resistant depression: a prospective randomized controlled trial.Brain Stimul. 2019; https://doi.org/10.1016/j.brs.2019.09.009Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. In this new PET analysis, we included 36 patients who completed 20 rTMS sessions, and underwent cerebral 18-FDG PET, at resting-state, one week before the start of the rTMS therapy (T0), and one week after the end of this treatment (T1). The left dorsolateral prefrontal cortex (dlPFC) was targeted according to the Beam F3 algorithm. Deep-rTMS and standard rTMS were performed at equal locations, durations and frequencies (acute phase of 4 weeks, at 10 Hz high frequency (HF), 2000 stimuli per session were delivered at 120% resting motor threshold in trains of 5-s stimulation followed by 25-s rest periods). The coil used for the standard rTMS protocol was a figure-eight coil (Cool-B65, Magventure A/S). A double-cone coil (Cool-D-B80, Magventure A/S) was selected for the deep-rTMS protocol. 18F-FDG PET was performed using an integrated PET/CT camera (Discovery 710, GE Healthcare, Waukeskha, WI, USA). 18F-FDG (150 MBq) was injected intravenously 30 minutes before the scan. PET images were acquired over a duration of 15 minutes. The primary outcome was the proportion of patients achieving a response defined as a reduction of 50% on the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to 4 weeks post inclusion. Secondary outcome measures were remission defined as a MADRS score <10, response on the Quick Inventory of Depressive Symptomatology Self-Report-16 items (QIDS-SR-16) and changes on the Medical Outcome Study Short Form (SF-12), including mental and physical composite scores (MCS and PCS). Whole-brain statistical analysis was performed at the voxel level using SPM12 software (Wellcome Department of Cognitive Neurology, University College, London, UK) after spatial normalization and smoothing (Full width at half maximum = 8 mm). SPM (T) maps were generated for comparison before and after rTMS therapy (p-voxel < 0.005 uncorrected, p-cluster < 0.05 uncorrected), between responders and non-responders, and between the two stimulation protocols. Mean values of metabolism were extracted at the individual level for significant cluster(s) to calculate correlations (Pearson correlation) with the previously described clinical scores. We identified 14 responders and 22 non-responders to rTMS therapy. The stimulation protocol did not influence baseline metabolic differences between responders and non-responders or the metabolic changes between T0 and T1. The comparisons before and after rTMS therapy showed an increased metabolism in the bilateral precuneus and right temporal lobe (k = 1481 voxels), including the fusiform gyrus, hippocampal region and amygdala, in the responders compared to the non-responders (Fig. 1a). Before treatment, the non-responders showed significant baseline hypometabolism in the bilateral caudate nucleus in comparison to the responders (k = 601 voxels) (Fig. 1b). The increase in metabolic values in the precuneus after rTMS was related to score improvements in the MADRS (r = −0.456, p = 0.005), the QIDS-SR-16 (r = −0.577, p < 0.001) and the SF-12 MCS (r = 0.353, p = 0.035). In addition, the increase in metabolic values in the right temporal lobe after rTMS was related to score improvements in the MADRS (r = -0.466, p = 0.004), the QIDS-SR-16 (r = -0,530, p = 0,001) and the SF-12 MCS (r = 0.337, p = 0.045). Finally, baseline metabolic values in the caudate nucleus predicted score improvements in the MADRS (r = −0.418, p = 0.011), the QIDS-SR-16 (r = −0.428, p = 0.009) and the SF-12 MCS (r = 0.417, p = 0.011). In response prediction, baseline metabolic values in the caudate nucleus showed a sensitivity of 78.57% and specificity of 86.36%. The robustness of the predictive score was confirmed with an AUC value of 0.896 (p < 0.0001) (Fig. 1c). A lower baseline bilateral caudate nucleus metabolism seemed to be associated with non-responsiveness as measured by the MADRS. Successful rTMS improvements resulted from metabolic increases in the precuneus and right temporal lobe. To our knowledge, the caudate nucleus has never been shown as a potential metabolic PET predictor of response to rTMS, but seems to be a promising connectivity marker. Kang et al. presented a resting-state study from a comparative left-dlPFC rTMS trial and showed reduced levels of dlPFC-left caudate connectivity predicted improvement in depressive symptoms [[4]Kang J.I. Lee H. Jhung K. Kim K.R. An S.K. Yoon K.-J. et al.Frontostriatal connectivity changes in major depressive disorder after repetitive transcranial magnetic stimulation: a randomized sham-controlled study.J Clin Psychiatr. 2016; 77: e1137-e1143https://doi.org/10.4088/JCP.15m10110Crossref PubMed Scopus (37) Google Scholar]. Moreover, Downar et al. demonstrated significantly lower left ventro-medial PFC-left caudate nucleus functional connectivity in 23 non-responders who underwent double-cone coil rTMS targeting the medial prefrontal cortex [[5]Downar J. Geraci J. Salomons T.V. Dunlop K. Wheeler S. McAndrews M.P. et al.Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.Biol Psychiatr. 2014; 76: 176-185https://doi.org/10.1016/j.biopsych.2013.10.026Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]. Our findings about post-treatment rTMS effects are in line with a previous PET study from Li et al. with the increase in precuneus functioning in responders [[6]Li C.-T. Wang S.-J. Hirvonen J. Hsieh J.-C. Bai Y.-M. Hong C.-J. et al.Antidepressant mechanism of add-on repetitive transcranial magnetic stimulation in medication-resistant depression using cerebral glucose metabolism.J Affect Disord. 2010; 127: 219-229https://doi.org/10.1016/j.jad.2010.05.028Crossref PubMed Scopus (82) Google Scholar]. Nevertheless, bilateral metabolic increases in the uncus, hippocampus and parahippocampal gyri have been described as post-rTMS effects but not particularly in responders compared to non-responders [[7]Philip N.S. Barredo J. Aiken E. Carpenter L.L. Neuroimaging mechanisms of therapeutic transcranial magnetic stimulation for major depressive disorder.Biol Psychiatr Cogn Neurosci Neuroimaging. 2018; 3: 211-222https://doi.org/10.1016/j.bpsc.2017.10.007Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. Li et al. also showed a decrease in left fusiform and parahippocampal gyrus metabolism in 13 responders who received 2 weeks of navigated add-on dlPFC rTMS [[6]Li C.-T. Wang S.-J. Hirvonen J. Hsieh J.-C. Bai Y.-M. Hong C.-J. et al.Antidepressant mechanism of add-on repetitive transcranial magnetic stimulation in medication-resistant depression using cerebral glucose metabolism.J Affect Disord. 2010; 127: 219-229https://doi.org/10.1016/j.jad.2010.05.028Crossref PubMed Scopus (82) Google Scholar]. In contrast, our results showed a global metabolic increase in the right temporal lobe in responders that was not limited to the medial and inferior areas. Our results suggest that add-on rTMS therapy could be particularly efficient by modulating limbic-cortical dysregulation. Indeed, the caudate nucleus is closely connected with the dlPFC. It takes part in biased processing of emotional information along with the amygdala through a salience network. The precuneus and hippocampus have been implicated mainly through a default mode network and could also contribute to low self-esteem and ruminations [[8]Drysdale A.T. Grosenick L. Downar J. Dunlop K. Mansouri F. Meng Y. et al.Resting-state connectivity biomarkers define neurophysiological subtypes of depression.Nat Med. 2017; 23: 28-38https://doi.org/10.1038/nm.4246Crossref PubMed Scopus (1069) Google Scholar]. Finally, the lateral temporal areas, including the fusiform gyri and middle temporal lobe, are linked with negative perception and recognition [[9]Surguladze S. Brammer M.J. Keedwell P. Giampietro V. Young A.W. Travis M.J. et al.A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder.Biol Psychiatr. 2005; 57: 201-209https://doi.org/10.1016/j.biopsych.2004.10.028Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar,[10]Surguladze S.A. El-Hage W. Dalgleish T. Radua J. Gohier B. Phillips M.L. Depression is associated with increased sensitivity to signals of disgust: a functional magnetic resonance imaging study.J Psychiatr Res. 2010; 44: 894-902https://doi.org/10.1016/j.jpsychires.2010.02.010Crossref PubMed Scopus (81) Google Scholar]. In conclusion, precuneus and right temporal lobe metabolic improvements correlate with a reduction in depressive symptoms after rTMS. Caudate nucleus baseline metabolism predicts symptom evolution. These results involve networks linked to emotional and cognitive symptoms of depression and suggest the utility of cerebral 18FDG PET in the appropriate selection of patients for rTMS therapy. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work has been carried out in the framework of DHU-Imaging thanks to the support of: the A*MIDEX project (no. ANR-11-IDEX-0001-02) (“Investissements d’Avenir” French Government program, managed by the French National Research Agency (ANR)), the Public Assistance Marseille Hospitals (AORC junior 2014), and a research grant from a French foundation for health research and innovation “ Fondation de l’Avenir ”.