European Psychiatry 30 (2015) 75–81

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Review

Developing cognitive-emotional training exercises as interventions for mood and anxiety disorders B.M. Iacoviello *, D.S. Charney Department of Psychiatry, Icahn School of Medicine, Mount Sinai, NY, USA

A R T I C L E I N F O

A B S T R A C T

Article history: Received 25 September 2014 Received in revised form 29 September 2014 Accepted 29 September 2014 Available online 28 October 2014

There is an urgent need for more effective treatments for mood and anxiety disorders. As our understanding of the cognitive and affective neuroscience underlying psychiatric disorders expands, so do opportunities to develop novel interventions that capitalize on the capacity for brain plasticity. Cognitive training is one such strategy. This paper provides the background and rationale for developing cognitive-emotional training exercises as an intervention strategy, and proposes guidelines for the development and evaluation of cognitive training interventions with a specific focus on major depressive disorder as an example. ß 2014 Elsevier Masson SAS. All rights reserved.

Keywords: Cognitive Emotional Training Plasticity Intervention

There is an urgent need for more effective treatments for mood and anxiety disorders. Major depressive disorder (MDD) is a particularly disabling mood disorder associated with significant morbidity, mortality and public health costs [37,79]. Despite the development of numerous pharmacotherapy and psychotherapy options for the treatment for MDD, roughly 30–40% of patients fail to achieve adequate therapeutic response to currently available treatments [65,74]. To address this need for novel treatments, a Concept Clearance was issued as part of the NIMH Strategic Plan in 2011 [51] for ‘‘research that translates emerging findings on the neuroscience and behavioral science of mental disorders into novel psychosocial (e.g., cognitive strategies and innovative behavioral approaches) and other non-pharmacological interventions. . . that will alter dysfunctional neural circuits and psychological processes underlying mental disorders to reduce symptoms’’. Fortunately, as our understanding of the intersection between neuroscience, cognitive science and psychiatry grows, so do opportunities for the development of innovative translational intervention strategies. In this paper, we describe the rationale and method for developing cognitive-emotional training interventions for mood and anxiety disorders, and provide an example for MDD.

* Corresponding author. One Gustave L Levy Pl, Box 1230, New York, NY 10029, USA. Tel.: +21 2 241 6383; fax: +21 2241 3354. E-mail address: [email protected] (B.M. Iacoviello). http://dx.doi.org/10.1016/j.eurpsy.2014.09.415 0924-9338/ß 2014 Elsevier Masson SAS. All rights reserved.

1. Harnessing brain plasticity Plasticity refers to the brain’s ability to change as a result of experience, and modify future responses to the same and related stimuli [60]. Plasticity can involve functional or structural changes: strengthening or weakening of connections between neurons, formation of new synapses or loss of existing ones [6,10], or in unusual circumstances altered birth and growth of new neurons. A fundamental component of how brain plasticity occurs is the synapse between nerve cells. Synaptogenesis and synaptic pruning refer to the idea that individual connections within the brain are constantly being removed or recreated, largely dependent upon how they are used [6,10]. If two nearby neurons often produce an impulse simultaneously, their cortical maps become integrated via the growth of new synapses or strengthening existing ones. Conversely, neurons that do not regularly produce simultaneous impulses form different maps and the synaptic connections between them weaken. Thus, with experience, the number and strength of synapses in the brain can change over time, influencing neural network functioning. Change in the intrinsic excitability of neurons, termed whole cell plasticity or homeostatic plasticity, is also an important contributor to brain plasticity [39]. Changes to ion channel function in the axon, dendrites, and cell body result in changes in the integration of excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). Modification of the electrical properties of neurons can affect synaptic

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integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. The growth of new neurons, also termed neurogenesis, may also play a part in brain plasticity, although the contribution of neurogenesis to brain plasticity is likely smaller compared to synaptic changes and homeostatic plasticity. Hippocampal neurogenesis has been demonstrated in non-human primates and humans [20,24], and the subventricular zone (SVZ) was identified as a site of neurogenesis and self-renewing neurons in the adult brain [47]. Along with the subgranular zone of dentate gyrus, the SVZ serves as a source of neural stem cells in the process of adult neurogenesis. Some have also suggested that adult neurogenesis occurs in regions within the brain not generally associated with neurogenesis including the neocortex [25,67,82]. Thus, evidence is emerging that neurogenesis occurs in the brain, with the strongest evidence for neurogenesis occurring in the dentate gyrus and subventricular zone. Together, synaptogenesis, synaptic pruning, homeostatic plasticity and, to a lesser degree neurogenesis begin to explain the mechanisms by which brain plasticity can occur on structural and functional levels. Studies suggest that cognitive interventions can influence brain plasticity. In a neonatal ventral hippocampal lesion rat model of schizophrenia, cognitive training in adolescent rats protected against cognitive control impairments and altered hippocampal neural activity typically observed in adulthood [43]. Human PET and fMRI studies of cognitive therapy for depression and anxiety have identified functional changes in neural circuits involved in cognitive control and emotion regulation [15], and implicit cognitive priming for emotional stimuli demonstrated a persistent effect on subsequent amygdala response [62]. A systems neuroscience rationale for cognitive training interventions has been proposed, emphasizing the distributed nature of neural circuits that support cognitive and affective processing, as well as their plasticity [75]. During successful learning neural circuitry is altered, cognitive/affective inputs and action outputs are represented by larger and more coordinated populations of neurons that are distributed throughout multiple brain regions and across multiple levels of processing. Cognitive interventions could affect changes in brain neurobiology and function, and such changes are consistent with clinical effect.

2. Prior approaches to target maladaptive cognition 2.1. Cognitive approaches that explicitly target maladaptive cognitive processes Explicitly addressing maladaptive cognition in the treatment of mood and anxiety disorders is not necessarily a novel intervention strategy. One example is cognitive therapy, where maladaptive core beliefs, cognitive distortions and automatic thought patterns are directly challenged and reformulated. Cognitive therapy has received much empirical support for its ability to alter cognition, affect brain changes, and improve symptoms [15]. Interpretation bias modification is another example in which patients are trained through repeated learning opportunities to make neutral or positive interpretations for ambiguous hypothetical events as opposed to the negative interpretations they would usually make [48]. Studies of healthy individuals suggest that interpretation biases can be modified to be more positive [48], and in clinical populations interpretation bias modification has been shown to significantly reduce negative interpretation biases, and this precedes mood improvement [5,30].

2.2. Cognitive approaches that implicitly target maladaptive cognitive processes Cognitive theories of anxiety hold that early, automatic orienting of attention toward particular classes of stimuli (e.g., threat cues) plays a critical role in the etiology and maintenance of anxious mood. In Attention Bias Modification (ABM; [3]), patients are implicitly trained to attend away from negatively-valenced stimuli and toward a simultaneously presented neutral stimulus. Studies have demonstrated that change in attention bias can result in significant improvement in anxiety symptoms [28]. This is consistent with the observation that anxious individuals show increased vigilance for threat during free viewing and visual search, and show difficulty disengaging from threat in visual search tasks. In contrast, depressed individuals tend not to show the same vigilance for threat during free viewing, but are characterized by reduced orienting to and maintenance of gaze on positive stimuli and increased maintenance of gaze on dysphoric stimuli [1]. Still, studies using ABM procedures have shown results reducing MDD symptoms [78,80]. The results of ABM studies for mood and anxiety symptoms must be considered with caution when they do not report changes in underlying attention biases while reporting improvements in clinical symptoms, raising questions about the mechanism of effect. Some have demonstrated that the direction of ABM training may not be important. In one study of socially anxious patients, attention training toward threat or away from threat, compared to no training, was associated with attenuated anxiety during a social stress induction challenge [38]. Perhaps exercising and training cognitive control for emotional information processing is the key mechanism of effect in ABM regardless of the direction of training. 2.3. Cognitive control training and neurobehavioral therapies Enhancing cognitive control has become a target for intervention in mood and anxiety disorders. Mindfulness training, in which patients are trained to bring awareness to their internal and external experiences in the present moment, is an example of attentional control training [73]. Mindfulness training has shown effects on cognitive processes, such as selective and executive attention [8] as well as clinical effects on mood, emotion regulation, decreased reactivity and increased flexibility of responses [2,12]. In 2007, Siegle et al. [71] reported that a metacognitive attention training exercise aimed at enhancing functioning of prefrontal cortical brain regions resulted in improvement in cognitive control and MDD symptoms. Others have since reported on the efficacy of this [7] and other similar cognitive or attentional training exercises [59] in dysphoric or depressed patients. These are examples of neurobehavioral therapies (NBT); therapies designed to target a known biological mechanism of the disorder using cognitive or behavioral techniques to affect change in that mechanism. Several lines of evidence provide support for the NBT concept:  cognitive and behavioral psychotherapies employ an analogous approach, directly target mechanisms (core beliefs, etc.) that underlie maladaptive thought and behavior patterns;  neurofeedback can effectively train patients to modulate their own neural activity, suggesting a cognitive exercise could affect change at the neurobiological or neural circuitry function level;  cognitive rehabilitation has shown promise in identifying affected brain regions and functions using neuropsychological testing and neuroimaging, and using targeted, repetitive behavioral exercises to strengthen aspects of cognition, such as attention, memory, and cognitive organization which have

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been impaired due to stroke, traumatic brain injury, and memory disorders. Research also suggests that by targeting and activating one component of a neural network, effects can be detected in other components. For example, stimulation of specific medial prefrontal cortex (mPFC) cells that project to the brainstem dorsal raphe nucleus (DRN) activated the DRN and induced a profound effect in a rat model of MDD [77]. Activating other mPFC cells that do not project to the DRN did not have this effect. Thus, there is emerging evidence for the utility of targeting one component of a neural network implicated in MDD to effect changes network-wide. 3. A framework for developing cognitive-emotional training interventions As mood and anxiety disorders involve maladaptive processing of emotionally salient information, we propose that targeted cognitive-emotional training interventions can be developed based on an understanding of the underlying psychopathology (particularly cognitive and affective processing biases) and associated pathophysiology (i.e., neural circuitry abnormalities), and employing brain plasticity. We propose five steps to guide the development of these interventions. 3.1. Five steps for developing a cognitive training intervention  Step 1: identify the underlying abnormality to address. This could include a variety of potential systems: neurobiology/ neural circuitry, abnormal cognitive processes, etc., and there should be some indication that the target plays a causal role in the onset of clinical symptoms.  Step 2: determine the components of the abnormality that are most amenable to targeting with a cognitive training activity. For example, certain brain regions within a particular neural network may be more amenable to change with a cognitive exercise than others.  Step 3: identify a cognitive activity/task believed to influence these components of interest. For example, emotion regulation tasks recruit certain brain regions; working memory exercises recruit others, etc. Identifying a cognitive activity that recruits and activates a particular brain region of interest allows for the development of a cognitive training regimen.  Step 4: devise a training regimen using the task repeatedly in a way that is progressively challenging, consistently engaging the system, and engendering plasticity through learning.  Step 5: evaluate the effects of the training on the underlying system/abnormality targeted and any relevant clinical symptoms. An example of this process in a non-clinical sample is a working memory training that showed effects improving working memory capacity as well as effects on fluid intelligence [32]. Although fluid intelligence was not directly trained, this study provided evidence for transfer from training on a working memory task to measures of fluid intelligence. An example in a clinical sample of MDD patients is a preliminary finding that a regimen of a training exercise designed to enhance cognitive control for emotional information processing showed effects reducing negative affective bias in short-term memory and MDD symptoms [31]. 4. Example: a cognitive-emotional training intervention strategy to target cognitive and emotion processing abnormalities in MDD Developing a cognitive-emotional training intervention for MDD requires identifying components of the neural circuitry

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implicated in MDD and targeting these brain regions with the use of cognitive strategies to enhance plasticity. For affective disorders, such as MDD, we propose that cognitive control specifically for emotional information processing is a particularly viable target. There is a direct connection between cognitive control abnormalities in emotional information processing and the psychopathology underlying mood and anxiety disorders, and we have an understanding of the underlying neural network functioning abnormalities associated with this deficit. 4.1. Step 1: identify the underlying abnormality to address A growing body of research associates MDD with abnormalities in cognitive control for emotional information processing and maladaptive emotion regulation. One way this manifests in MDD is in biased and prolonged processing of negative emotional information including a tendency to ruminate or perseverate on mood-congruent information [54]; ruminative tendencies are also associated with vulnerability for MDD onset and recurrence [54]. Increased interference from negative affective information in cognitive processing [36], and impairments in inhibitory control specifically for negative affective information result in a cognitively inflexible depressive mindset and the perseverative thinking observed in rumination [13]. Recent studies suggest that impairments in filtering and inhibitory control are more fundamental to the dysphoric mood state than was previously assumed [58], and that these impairments can be amenable to cognitive training interventions with effects observable at the neural and behavioral levels [59]. Taken together, we hypothesize that enhancing cognitive control for emotional information processing could result in improved emotion regulation, reduced rumination and antidepressant effects. 4.2. Step 2: determine the cognitive training targets Neuroimaging studies of emotional information processing and emotion regulation demonstrate that relative to healthy controls (HC) individuals with MDD show hyperactivation of subcortical neural systems implicated in emotion perception and responses and hypoactivation of cortical systems implicated in cognitive control and emotion regulation [18,49,61,66,68,72,63]. Subcortical systems involved in emotion perception, generation of negative affect, and subsequent responses (e.g., the amygdala and nucleus accumbens) have long been a focus of research in MDD; prefrontal cortical (PFC) structures involved in regulation of emotion and cognitive control are emerging as critical to the disease state and antidepressant response [22,27,40,44,45,69,81]. Dorsolateral PFC (DLPFC) in particular is critical for cognitive control, rumination, emotion regulation and working memory, which are all impaired in MDD and are functionally inter-related [4,34,42,55–57,76]. Specific neural circuitry abnormalities have been suggested to underlie the biased and prolonged processing of negative affective information observed in MDD [16]. Emotional information, upon perception, is relayed to the thalamus, which projects directly to the amygdala among other regions [41]. The amygdala evaluates the emotional salience of the stimuli, and is regulated indirectly by inhibitory input from the DLPFC [11,17]. In healthy individuals, amygdala activity increases during the processing of emotional information [17] and shows an inverse relationship with DLPFC activity [9,11,21,70]. In MDD, amygdala reactivity is observed to increase beyond HC levels [17,70]. In addition, the DLPFC and dorsal anterior cingulate cortex (ACC), which relays top-down cognitive control from the PFC [55], show reduced activity during emotional information processing [17,21,23], suggesting reduced inhibitory feedback to and cognitive control over the amygdala [26]. Limbic feedback proceeding through

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bottom-up pathways including the subgenual cingulate cortex (SGC) [26] to higher-order regions with less inhibition results in preferential processing of negative affective information and reduced cognitive control for emotional information processing. Hyperactivity of the amygdala and hippocampus, proximal structures that exhibit mutual facilitation during the processing of emotional stimuli, and sustained activity of the subgenual cingulate cortex, result in prolonged emotional experience. Increased activity in the medial prefrontal cortex (mPFC), which projects directly to the amygdala, houses the internal representation of the self and is associated with self-referential thought [14,22,26,27,64] is also observed in MDD and is associated with a tendency to interpret negative affective information as selfrelevant and salient to the individual [14,64]. Reduced responsiveness of the reward system, and particularly the nucleus accumbens (NAcc) has also been shown in MDD [19]. Associations between the NAcc and PFC regions that trigger dopamine release and influence NAcc activity in non-depressed individuals are attenuated in MDD [29], contributing to impaired processing of the rewarding attributes or positive valence of stimuli [52] and reduced positive affect. Moreover, decreased NAcc and PFC activity is most prominent when MDD patients attempt to consciously upregulate or sustain positive mood [29], suggesting impaired top-down cognitive control of positive affect as well as negative affect. The NAcc also receives inputs from the amygdala and hippocampus as it evaluates the emotional salience of stimuli, and projects back to the thalamus. Reduced responsiveness of the NAcc may impair the brain’s ability to evaluate and encode the positive valence of stimuli, contributing to the negative affective bias in stimulus perception and processing. Taken together, biased and prolonged processing of negative emotional information in MDD may be facilitated by impaired topdown cognitive control over limbic brain regions, which is associated with hypoactivation of DLPFC/VLPFC regions. Therefore, a cognitive-emotional training strategy might aim to enhance function of the PFC/DLPFC to inhibit and overcome aberrant limbic activity during emotional information processing and the

subsequent biased and prolonged processing of negative emotional information (see Fig. 1). 4.3. Step 3: identify a cognitive activity/task believed to influence the components of interest Cognitive activities relying on (and inducing activity in) the components of the neural circuitry described above include working memory and emotional information processing (for example, identifying emotions). To target and enhance functioning of the DLPFC, we propose a working memory exercise. To simultaneously target limbic system function, we propose to combine emotion identification and working memory activities into a single cognitive exercise. Working memory is a system that provides temporary access to a select set of representations for current cognitive processes [50], and recent studies suggest that deficits in working memory for emotional material are associated with cognitive inflexibility and underlie ruminative responses in MDD [35]. In addition, one well-established information processing bias in MDD is a negative affective bias for working memory. This bias is manifest in several ways: preferential memory for negative versus positive emotional information in short-term, selfrelevant tasks [33]; impaired ability to expel irrelevant negative information from working memory and impaired selection of relevant positive content among competing stimuli in working memory [46]. Working memory impairment in MDD is specific to emotional information, predicts the degree of rumination experienced, and is associated with depression symptom severity [36]. We hypothesize that exercising the ability to manipulate emotional information in working memory could enhance cognitive control for emotional material and emotion regulation, reduce rumination, and have antidepressant effects. The exercise proposed is a combination of emotion identification and working memory tasks. In this task, participants must identify the emotions they observe on a string of faces presented on a computer screen, and remember the sequence of emotions. Using an n-back working memory training paradigm, for each face observed

Fig. 1. A cognitive neurobiological model for negatively biased and prolonged processing of emotional information in MDD. In MDD, hyperactivation of the thalamus (THAL), amygdala (AMY) and hippocampus (HIPP) upon perception of emotionally salient stimuli is associated with increased subgenual cingulate (SGC) activity, which integrates limbic feedback and relays to the prefrontal cortex (PFC). SGC activity is also associated with increased medial PFC (MPFC) activity, which is associated with self-referential information processing. Concurrently, activity is decreased in PFC regions (DLPFC, VLPFC) and the dorsal anterior cingulate cortex (DACC), associated with cognitive control. Activity is also decreased in the nucleus accumbens (NACC), which assigns positive or rewarding valence to stimuli. Functional connectivity between PFC and other regions (AMY, HIPP, NACC) appears attenuated, indicating inefficient cognitive control over these regions. The net result of the hyperactive negative emotion perception, processing and elaboration, and impaired cognitive control, is biased and prolonged processing of negatively-valenced information. Solid arrows (showing intact associations) and dashed arrows (showing attenuated associations) represent functional connections. Dashed arrows indicate functional connectivity abnormalities resulting in impaired cognitive control, and represent targets for cognitive training interventions.

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participants indicate whether the emotion is the same as the emotion n faces back. The n level varies by block depending on performance; n can decrease or increase across blocks and participants complete many blocks per session. The task effectively hones in on the participants ability level while consistently challenging them. A version of this task has been shown to simultaneously recruit PFC structures involved in working memory and limbic structures involved in emotion processing (amygdala) [53] in a single, non-progressive session in healthy volunteers. 4.4. Step 4: devise a training regimen The cognitive training regimen should involve many repetitions of the exercise within a session and over time. The regimen should be frequent enough to engender learning and plasticity of the neural circuitry involved. We propose a training regimen of at least 2–3 sessions per week, for 4 weeks minimum, in line with previous cognitive training regimens reported in the literature [3,28]. Sessions will involve hundreds of presentations of stimuli across many blocks. Session 1 begins with n = 1 and as noted above the difficulty level can change each block based on performance; the starting n for subsequent sessions is determined by performance at the prior session. 4.5. Step 5: evaluate the effects of the training on underlying mechanisms and MDD symptoms We propose that the effectiveness of the cognitive-emotional training regimen should be evaluated using a battery of measures to assess:  changes in the functioning of neural network being targeted (for example, fMRI analysis of amygdala/DLPFC functional connectivity during emotion regulation);  changes in cognitive biases and rumination;  changes in neurocognition/working memory;  changes in MDD symptoms. 5. Considerations for evaluating a cognitive-emotional training intervention for MDD Several research design considerations are worth noting for future investigations of cognitive-emotional training interventions.

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effects; on the other hand, synergistic effects between medications and cognitive training are conceivable. Recruiting only participants currently using stable antidepressant regimens may mitigate the risk of obscuring training effects, and this approach is common in clinical trials. 5.3. Outcome measures Should include a variety of cognitive and emotional processing measures, as well as behavioral measures and MDD symptom measures, to identify specific changes resulting from the training. These could include measures of verbal memory capability, working memory, cognitive bias, rumination, cognitive control and emotion processing. Outcome measures could be administered at midpoints in the training regimen, as well as at baseline and study completion. 5.4. Subsequent steps Would be indicated after proof-of-concept studies to determine the efficacy of the training intervention in comparison to existing interventions. Studies of the time-course and durability of cognitive training effects would also be warranted. 6. Conclusion As our understanding of the cognitive and affective neuroscience underlying psychiatric disorders expands, so to do opportunities to develop novel intervention strategies that seek to harness the capacity for brain plasticity. Cognitive bias modification and cognitive therapies are examples of such strategies that have been gaining empirical support. However, the development of cognitive training exercises as neurobehavioral therapies, with specific underlying neural circuitry targets informed by basic research into the pathophysiology of the disorder, are in their infancy and further research is clearly warranted. This paper sought to set out guidelines for the development and evaluation of cognitive training interventions. As we begin to further understand their effects and the mechanisms by which these interventions can effect improvement, future studies could conceivably involve investigating the synergistic effects of cognitive training and pharmacotherapy, or other methods for enhancing and maintaining the effects of cognitive training interventions.

5.1. Control/comparison groups As with any intervention study, special attention should be paid to the placebo or other control group that will be included in the study. Ideally, the control comparison will involve a cognitive training exercise that is as similar as possible to the investigational training exercise, without having the same (hypothesized) effects. A control training exercise for investigating the cognitiveemotional training described above could be identical to the investigational exercise, except the stimuli are neutral shapes not emotional faces. This would allow for comparison of the investigational training regimen to a working memory training regimen (the control regimen) that does not involve emotional identification and processing, thereby not recruiting limbic structures, and thus isolating the effect of the simultaneous activation of DLPFC/amygdala in the investigational training group. 5.2. Concomitant medications Researchers should consider whether to include patients in their studies that are also prescribed psychotropic medications. Effects of these medications could obscure the cognitive training

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