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Neural predictors of treatment response to brain stimulation and psychological therapy in depression: a double-blind randomized controlled trial


Standard depression treatments, including antidepressant medication and cognitive behavioural therapy (CBT), are ineffective for many patients. Prefrontal transcranial direct current stimulation (tDCS) has been proposed as an alternative treatment, but has shown inconsistent efficacy for depression, and its mechanisms are poorly understood. We recruited unmedicated patients with major depressive disorder (N = 71 approached; N = 39 randomised) for a mechanistic, double-blind, randomized controlled trial consisting of eight weekly sessions of prefrontal tDCS administered to the left prefrontal cortex prior to CBT. We probed (1) whether tDCS improved the efficacy of CBT relative to sham stimulation; and (2) whether neural measures predicted clinical response. We found a modest and non-significant effect of tDCS on clinical outcome over and above CBT (active: 50%; sham: 31.6%; odds ratio: 2.16, 95% CI = 0.59–7.99), but a strong relationship, predicted a priori, between baseline activation during a working memory task in the stimulated prefrontal region and symptom improvement. Repeating our analyses of symptom outcome splitting the sample according to this biomarker revealed that tDCS was significantly superior to sham in individuals with high left prefrontal cortex activation at baseline; we also show 86% accuracy in predicting clinical response using this measure. Exploratory analyses revealed several other regions where activation at baseline was associated with subsequent response to CBT, irrespective of tDCS. This mechanistic trial revealed variable, but predictable, clinical effects of prefrontal tDCS combined with CBT for depression. We have discovered a potential explanation for this variability: individual differences in baseline activation of the region stimulated. Such a biomarker could potentially be used to pre-select patients for trials and, eventually, in the clinic.

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Data availability

All data discussed in the paper will be made available to any reader who enters into a managed access arrangement. Ethical and data governance restrictions prevent the data from being shared in a public repository (all data are patient data collected under UK National Health Service ethics and patients did not give consent for open sharing). All data will be shared freely following a formal Data Sharing Agreement with University College London. Researchers who wish to access the data should contact the senior author (

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Trial Registration: The trial was registered at, registration number NCT01875419; URL:


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The authors would like to thank research assistants Jessica Alylward and Alan Gray for their help with data collection. They are also extremely grateful to the NHS clinicians Michaela Thomas, Dr Chinea Eziefula, Carlo Gittens, Laura Franklin, Dr Karen Katz, Dr Robin Weedon, Dr Jeremy Handel, Dr Flavia Cigolla, Akbar Jamil, Dr Isabella Foustanos, Dr Abi Harris, Dr Sukhvinder Virdee, Dr Jessica Wilner-Reid, and Dr Joshua Buckman, as well as all the patients who generously volunteered their time for the trial.

Author information

CLN, JPR, NL, SP, VV, and CC designed the study, CLN, CH, TL, and JL collected data, CLN analysed data, CLN and JPR wrote the paper with contributions from all the other authors.

Competing interests

The authors declare no competing interests.

Correspondence to Camilla L. Nord.

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