Predicting Response to Brain Stimulation in Depression: a Roadmap for Biomarker Discovery

Abstract: Purpose of Review: Clinical response to brain stimulation treatments for depression is highly variable. A major challenge for the field is predicting an individual patient’s likelihood of response. This review synthesises recent developments in neural predictors of response to targeted brain stimulation in depression. It then proposes a framework to evaluate the clinical potential of putative ‘biomarkers’. Recent Findings: Largely, developments in identifying putative predictors emerge from two approaches: data-driven, including machine learning algorithms applied to resting state or structural neuroimaging data, and theory-driven, including task-based neuroimaging. Theory-driven approaches can also yield mechanistic insight into the cognitive processes altered by the intervention. Summary: A pragmatic framework for discovery and testing of biomarkers of brain stimulation response in depression is proposed, involving (1) identification of a cognitive-neural phenotype; (2) confirming its validity as putative biomarker, including out-of-sample replicability and within-subject reliability; (3) establishing the association between this phenotype and treatment response and/or its modifiability with particular brain stimulation interventions via an early-phase randomised controlled trial RCT; and (4) multi-site RCTs of one or more treatment types measuring the generalisability of the biomarker and confirming the superiority of biomarker-selected patients over randomly allocated groups

Predicting Response to Brain Stimulation in Depression: a Roadmap for Biomarker Discovery

Abstract: Purpose of Review: Clinical response to brain stimulation treatments for depression is highly variable. A major challenge for the field is predicting an individual patient’s likelihood of response. This review synthesises recent developments in neural predictors of response to targeted brain stimulation in depression. It then proposes a framework to evaluate the clinical potential of putative ‘biomarkers’. Recent Findings: Largely, developments in identifying putative predictors emerge from two approaches: data-driven, including machine learning algorithms applied to resting state or structural neuroimaging data, and theory-driven, including task-based neuroimaging. Theory-driven approaches can also yield mechanistic insight into the cognitive processes altered by the intervention. Summary: A pragmatic framework for discovery and testing of biomarkers of brain stimulation response in depression is proposed, involving (1) identification of a cognitive-neural phenotype; (2) confirming its validity as putative biomarker, including out-of-sample replicability and within-subject reliability; (3) establishing the association between this phenotype and treatment response and/or its modifiability with particular brain stimulation interventions via an early-phase randomised controlled trial RCT; and (4) multi-site RCTs of one or more treatment types measuring the generalisability of the biomarker and confirming the superiority of biomarker-selected patients over randomly allocated groups

Reliability of Fronto-Amygdala Coupling during Emotional Face Processing.

One of the most exciting translational prospects for brain imaging research is the potential use of functional magnetic resonance imaging (fMRI) 'biomarkers' to predict an individual's risk of developing a neuropsychiatric disorder or the likelihood of responding to a particular intervention. This proposal depends critically on reliable measurements at the level of the individual. Several previous studies have reported relatively poor reliability of amygdala activation during emotional face processing, a key putative fMRI 'biomarker'. However, the reliability of amygdala connectivity measures is much less well understood. Here, we assessed the reliability of task-modulated coupling between three seed regions (left and right amygdala and the subgenual anterior cingulate cortex) and the dorsomedial frontal/cingulate cortex (DMFC), measured using a psychophysiological interaction analysis in 29 healthy individuals scanned approximately two weeks apart. We performed two runs on each day of three different emotional face-processing tasks: emotion identification, emotion matching, and gender classification. We tested both between-day reliability and within-day (between-run) reliability. We found good-to-excellent within-subject reliability of amygdala-DMFC coupling, both between days (in two tasks), and within day (in one task). This suggests that disorder-relevant regional coupling may be sufficiently reliable to be used as a predictor of treatment response or clinical risk in future clinical studies

Prefrontal cortex stimulation does not affect emotional bias, but may slow emotion identification

Transcranial direct current stimulation (tDCS) has recently garnered attention as a putative depression treatment. However, the cognitive mechanisms by which it exerts an antidepressant effect are unclear: tDCS may directly alter ‘hot’ emotional processing biases, or alleviate depression through changes in ‘cold’ (non-emotional) cognitive function. Here, 75 healthy participants performed a facial emotion identification task during 20 minutes of anodal or sham tDCS over the left dorsolateral prefrontal cortex (DLPFC) in a double-blind, within-subject crossover design. A subset of 31 participants additionally completed a task measuring attentional distraction during stimulation. Compared to sham stimulation, anodal tDCS of the left DLPFC resulted in an increase in response latency across all emotional conditions. Bayesian analysis showed definitively that tDCS exerted no emotion-dependent effect on behaviour. Thus, we demonstrate that anodal tDCS produces a general, rather than an emotion-specific, effect. We also report a preliminary finding in the subset of participants who completed the distractibility task: increased distractibility during active stimulation correlated significantly with the degree to which tDCS slowed emotion identification. Our results provide insight into the possible mechanisms by which DLPFC tDCS may treat symptoms of depression, suggesting that it may not alter emotional biases, but instead may affect ‘cold’ cognitive processes

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [F-18]FDOPA, [C-11]MADAM and [C-11]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [C-11]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

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.This work was supported by the Brain and Behavior Research Foundation (grant number 20162) to JPR and a Brain Research Trust PhD studentship awarded to CLN, and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (SP). JPR consults for Cambridge Cognition, Takeda Ltd and GE

RAISE study protocol: a cross-sectional, multilevel, neurobiological study of resilience after individual stress exposure

Introduction: This paper describes the protocol for an ongoing project funded by the Royal Society, the Resilience After Individual Stress Exposure (RAISE) study; which aims to examine the factors and mechanisms that facilitate resilient functioning after childhood adversity (CA). Methods and analysis: We aim to recruit up to 200 participants. We will use dimension reduction techniques (principal component analysis) on standard-normally transformed individual parameters of mental health, social functioning and CA to calculate a composite measure of adaptive (ie, ‘resilient’) psychosocial functioning. To examine the neuroimmune responses to stress and their relationship with the brain and social environment, we will use a well validated functional MRI task; the Montreal imaging stress task and venepuncture. We will run group or dimensional comparisons in multiple levels of biological and psychological outcomes, as well as mediation and moderation analyses to study how key biological systems (ie, the hypothalamic–pituitary–adrenal axis and the immune system) interrelate and interact with brain function and social influences in order to facilitate resilient functioning after CA. We hypothesise that resilient functioning will be facilitated by reduced morning cortisol and cytokine levels before and after the stressor and improved neural responses to such stress, as well as increased gray matter volume in the hippocampus and prefrontal cortex, enhanced inhibitory control and emotion regulation, and more friendship and family support. Ethics and dissemination: This study has been reviewed and given favourable opinion by the National Research Ethics Service, NRES Committee East of England-Cambridge Central and external reviewers from the Royal Society (RGF\R1\180064 and RGF\EA\180029). The results of the RAISE study will be disseminated through (1) publications in scientific peer reviewed journals, (2) presentations on relevant scientific conferences and meetings, (3) publications and presentations for the general public and (4) through social media