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

The role of dorsolateral prefrontal cortex dysfunction in depression and its treatment with non-invasive brain stimulation

Major depression is a common and debilitating condition. However, initial treatment is ineffective for almost half of all patients. This thesis aims to clarify the mechanisms of a novel putative treatment for depression, transcranial direct current stimulation (tDCS), which targets the dorsolateral prefrontal cortex (DLPFC). The first experimental chapter tests whether DLPFC tDCS alters emotional face perception, akin to the acute effects of antidepressant drugs. Our analyses revealed that tDCS does not exert an antidepressant-like effect on emotion perception, but may affect non-emotional cognition. The second experimental chapter examines neural activation in depressed patients, unaffected first-degree relatives of depressed patients, and healthy controls during the n-back working memory task and a facial emotion processing task. During the n-back, depressed patients showed pronounced DLPFC hypoactivation, while at-risk participants were indistinguishable from healthy controls, consistent with the hypothesis that DLPFC dysfunction might be a useful target for depression treatment. In the final two chapters, I report results from a double-blind randomized controlled trial that for the first time tested DLPFC tDCS as an augmentation strategy to psychotherapy in depression, measuring its neural, cognitive, and clinical effects. On the primary outcome measure (observer-rated depressive symptoms) active tDCS did not show a significant improvement over sham stimulation, although the difference was in the hypothesised direction. However, baseline DLPFC activation during the n-back strongly predicted clinical outcome, with this association specific to the active tDCS condition. Thus, baseline DLPFC activation might serve as a putative ‘biomarker’ for clinical response to tDCS. In the general discussion, these experimental findings are discussed in the context of contemporary theories of depression. This thesis adds new insights into the possible mechanisms of tDCS as a treatment for depression. It also demonstrates the added value of neuroimaging to psychiatry clinical trials, highlighting a potential role for predicting treatment outcome

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

Teaching and learning addition and subtraction bridging through ten using a structural approach

An eight-month-long intervention based on the idea of using a structural approach to addition and subtraction, and particularly bridging through ten, was implemented in Swedish Grade 1. A goal was that at the end of Grade 1, students would solve tasks like 15–7= using part-whole relations of numbers. In this paper, we report on learning outcomes from task-based interviews with intervention and control groups before, immediately after and one year after the intervention, to investigate long-term effects and whether students used a structural approach when solving tasks in Grade 2. Results show that students in the intervention group increased their learning outcomes the most and to a larger extent solved tasks in higher number ranges using a structural approach.This work was supported by the Swedish Institute for Educational Research [Grant number 2018-00038]

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