Refining our understanding of depressive states and state transitions in response to cognitive behavioural therapy using latent Markov modelling.

BACKGROUND: It is increasingly recognized that existing diagnostic approaches do not capture the underlying heterogeneity and complexity of psychiatric disorders such as depression. This study uses a data-driven approach to define fluid depressive states and explore how patients transition between these states in response to cognitive behavioural therapy (CBT). METHODS: Item-level Patient Health Questionnaire (PHQ-9) data were collected from 9891 patients with a diagnosis of depression, at each CBT treatment session. Latent Markov modelling was used on these data to define depressive states and explore transition probabilities between states. Clinical outcomes and patient demographics were compared between patients starting at different depressive states. RESULTS: A model with seven depressive states emerged as the best compromise between optimal fit and interpretability. States loading preferentially on cognitive/affective v. somatic symptoms of depression were identified. Analysis of transition probabilities revealed that patients in cognitive/affective states do not typically transition towards somatic states and vice-versa. Post-hoc analyses also showed that patients who start in a somatic depressive state are less likely to engage with or improve with therapy. These patients are also more likely to be female, suffer from a comorbid long-term physical condition and be taking psychotropic medication. CONCLUSIONS: This study presents a novel approach for depression sub-typing, defining fluid depressive states and exploring transitions between states in response to CBT. Understanding how different symptom profiles respond to therapy will inform the development and delivery of stratified treatment protocols, improving clinical outcomes and cost-effectiveness of psychological therapies for patients with depression.

The effects of transcranial direct current stimulation on within- and cross-paradigm transfer following multi-session backward recall training.

Transcranial direct current stimulation (tDCS) has been shown to enhance the efficacy and generalisation of working memory (WM) training, but there has been little systematic investigation into how coupling task-specific WM training with stimulation impacts more specifically on transfer to untrained tasks. This randomised controlled trial investigated the boundary conditions to transfer by testing firstly whether the benefits of training on backward digit recall (BDR) extend to untrained backward recall tasks and n-back tasks with different materials, and secondly which, if any, form of transfer is enhanced by tDCS. Forty-eight participants were allocated to one of three conditions: BDR training with anodal (10 min, 1 mA) or sham tDCS, or visual search training with sham tDCS, applied over the left dorsolateral prefrontal cortex. Transfer was assessed on within- (backward recall with digits, letters, and spatial locations) and cross-paradigm (n-back with digits and letters) transfer tests following three sessions of training and stimulation. On-task training gains were found, with transfer to other backward span but not n-back tasks. There was little evidence that tDCS enhanced on-task training or transfer. These findings indicate that training enhances paradigm-specific processes within WM, but that tDCS does not enhance these gains.

Quantifying the Association Between Psychotherapy Content and Clinical Outcomes Using Deep Learning.

Importance: Compared with the treatment of physical conditions, the quality of care of mental health disorders remains poor and the rate of improvement in treatment is slow, a primary reason being the lack of objective and systematic methods for measuring the delivery of psychotherapy. Objective: To use a deep learning model applied to a large-scale clinical data set of cognitive behavioral therapy (CBT) session transcripts to generate a quantifiable measure of treatment delivered and to determine the association between the quantity of each aspect of therapy delivered and clinical outcomes. Design, Setting, and Participants: All data were obtained from patients receiving internet-enabled CBT for the treatment of a mental health disorder between June 2012 and March 2018 in England. Cognitive behavioral therapy was delivered in a secure online therapy room via instant synchronous messaging. The initial sample comprised a total of 17 572 patients (90 934 therapy session transcripts). Patients self-referred or were referred by a primary health care worker directly to the service. Exposures: All patients received National Institute for Heath and Care Excellence-approved disorder-specific CBT treatment protocols delivered by a qualified CBT therapist. Main Outcomes and Measures: Clinical outcomes were measured in terms of reliable improvement in patient symptoms and treatment engagement. Reliable improvement was calculated based on 2 severity measures: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder 7-item scale (GAD-7), corresponding to depressive and anxiety symptoms respectively, completed by the patient at initial assessment and before every therapy session (see eMethods in the Supplement for details). Results: Treatment sessions from a total of 14 899 patients (10 882 women) aged between 18 and 94 years (median age, 34.8 years) were included in the final analysis. We trained a deep learning model to automatically categorize therapist utterances into 1 or more of 24 feature categories. The trained model was applied to our data set to obtain quantifiable measures of each feature of treatment delivered. A logistic regression revealed that increased quantities of a number of session features, including change methods (cognitive and behavioral techniques used in CBT), were associated with greater odds of reliable improvement in patient symptoms (odds ratio, 1.11; 95% CI, 1.06-1.17) and patient engagement (odds ratio, 1.20, 95% CI, 1.12-1.27). The quantity of nontherapy-related content was associated with reduced odds of symptom improvement (odds ratio, 0.89; 95% CI, 0.85-0.92) and patient engagement (odds ratio, 0.88, 95% CI, 0.84-0.92). Conclusions and Relevance: This work demonstrates an association between clinical outcomes in psychotherapy and the content of therapist utterances. These findings support the principle that CBT change methods help produce improvements in patients' presenting symptoms. The application of deep learning to large clinical data sets can provide valuable insights into psychotherapy, informing the development of new treatments and helping standardize clinical practice.

Psychopathic traits influence amygdala-anterior cingulate cortex connectivity during facial emotion processing.

There is accumulating evidence that youths with antisocial behavior or psychopathic traits show deficits in facial emotion recognition, but little is known about the neural mechanisms underlying these impairments. A number of neuroimaging studies have investigated brain activity during facial emotion processing in youths with Conduct Disorder (CD) and adults with psychopathy, but few of these studies tested for group differences in effective connectivity-i.e. changes in connectivity during emotion processing. Using functional magnetic resonance imaging and psycho-physiological interaction methods, we investigated the impact of CD and psychopathic traits on amygdala activity and effective connectivity in 46 male youths with CD and 25 typically-developing controls when processing emotional faces. All participants were aged 16-21 years. Relative to controls, youths with CD showed reduced amygdala activity when processing angry or sad faces relative to neutral faces, but the groups did not significantly differ in amygdala-related effective connectivity. In contrast, psychopathic traits were negatively correlated with amygdala-ventral anterior cingulate cortex connectivity for angry vs neutral faces, but were unrelated to amygdala responses to angry or sad faces. These findings suggest that CD and psychopathic traits have differential effects on amygdala activation and functional interactions between limbic regions during facial emotion processing.

Repetition Suppression and Memory for Faces is Reduced in Adults with Autism Spectrum Conditions.

Autism spectrum conditions (ASC) are associated with a number of atypicalities in face processing, including difficulties in face memory. However, the neural mechanisms underlying this difficulty are unclear. In neurotypical individuals, repeated presentation of the same face is associated with a reduction in activity, known as repetition suppression (RS), in the fusiform face area (FFA). However, to date, no studies have investigated RS to faces in individuals with ASC, or the relationship between RS and face memory. Here, we measured RS to faces and geometric shapes in individuals with a clinical diagnosis of an ASC and in age and IQ matched controls. Relative to controls, the ASC group showed reduced RS to faces in bilateral FFA and reduced performance on a standardized test of face memory. By contrast, RS to shapes in object-selective regions and object memory did not differ between groups. Individual variation in face-memory performance was positively correlated with RS in regions of left parietal and prefrontal cortex. These findings suggest difficulties in face memory in ASC may be a consequence of differences in the way faces are stored and/or maintained across a network of regions involved in both visual perception and short-term/working memory.

Transcranial Random Noise Stimulation Does Not Enhance the Effects of Working Memory Training.

Transcranial random noise stimulation (tRNS), a noninvasive brain stimulation technique, enhances the generalization and sustainability of gains following mathematical training. Here it is combined for the first time with working memory training in a double-blind randomized controlled trial. Adults completed 10 sessions of Cogmed Working Memory Training with either active tRNS or sham stimulation applied bilaterally to dorsolateral pFC. Training was associated with gains on both the training tasks and on untrained tests of working memory that shared overlapping processes with the training tasks, but not with improvements on working memory tasks with distinct processing demands or tests of other cognitive abilities (e.g., IQ, maths). There was no evidence that tRNS increased the magnitude or transfer of these gains. Thus, combining tRNS with Cogmed Working Memory Training provides no additional therapeutic value.

Intact priors for gaze direction in adults with high-functioning autism spectrum conditions.

BACKGROUND: Autism Spectrum Conditions (ASC) are associated with a range of perceptual atypicalities, including abnormalities in gaze processing. Pellicano and Burr (Trends Cogn Sci 16(10):504-10, 2012) have argued that these atypicalities might be explained within a Bayesian framework, in which perception represents the combination of sensory information with prior knowledge. They propose that the Bayesian priors of individuals with ASC might be attenuated, such that their perception is less reliant on prior knowledge than neurotypical individuals. An important tenet of Bayesian decision theory is that increased uncertainty about incoming sensory information will lead to a greater influence of the prior on perception. Consistent with this, Mareschal et al. (Curr Biol 23(8):717-21, 2013) showed that when noise is added to the eyes of a face (increasing uncertainty about gaze direction), gaze is more likely to be perceived as direct. METHODS: We adopted the same paradigm as Mareschal et al. to determine whether the influence of a prior on gaze perception is reduced in neurotypical participants with high numbers of autistic traits (experiment 1) and in individuals with a clinical diagnosis of ASC (experiment 2). Participants were presented with synthetic faces and asked to make a judgement about the relative gaze directions of the faces. Uncertainty about gaze direction was manipulated by adding noise to the eyes of a face. RESULTS: Consistent with previous work, in both experiment 1 and experiment 2, participants showed a bias towards perceiving gaze as direct under conditions of uncertainty. However, there was no evidence that the magnitude of this bias was reduced either in the ASC group or in neurotypical controls with a high number of autistic traits. CONCLUSIONS: Our findings challenge the attenuated priors theory of perception in ASC (Trends Cogn Sci 16(10):504-10, 2012) and related proposals (Trends Cogn Sci 17(1):1, 2013, Front Hum Neurosci 8:302, 2014), and suggest priors for gaze direction are intact in high-functioning ASC.

The effect of perceptual expectation on repetition suppression to faces is not modulated by variation in autistic traits.

There is substantial variation in the magnitude of the repetition suppression (RS) effects across individuals; however the causes of this variation remain unclear. In a recent study, we found that RS in occipitotemporal cortex was negatively related to individual variation in autistic traits in a neurotypical population. Recent proposals have considered autistic behaviours within a Bayesian framework, suggesting that individuals with autism may have 'attenuated priors' (i.e., their perception is less influenced by prior information). Predictive coding represents a neural instantiation of Bayesian inference, and characterises RS as reduction in prediction error between 'top-down' (prior beliefs) and 'bottom-up' (stimulus related) inputs. In accordance with this, evidence shows that RS is greater when repetition of a stimulus is expected relative to when it is unexpected. Here, using an established paradigm which manipulates the probability of stimulus repetition, we investigated the effect of perceptual expectation on RS in a group of neurotypical individuals varying on a measure of autistic traits. We predicted that the magnitude of the perceptual expectation effect would be negatively related to individual differences in autistic traits. We found a significant effect of perceptual expectation on RS in face-selective regions (i.e., greater RS when repetitions were expected relative to unexpected). However, there was no evidence of a relationship between autistic traits and the magnitude of this effect in any face-selective region of interest (ROI). These findings provide a challenge for the proposal that autism spectrum conditions (ASC) may be associated with the attenuated influence of prior information.

Repetition Suppression in Ventral Visual Cortex Is Diminished as a Function of Increasing Autistic Traits.

Repeated viewing of a stimulus causes a change in perceptual sensitivity, known as a visual aftereffect. Similarly, in neuroimaging, repetitions of the same stimulus result in a reduction in the neural response, known as repetition suppression (RS). Previous research shows that aftereffects for faces are reduced in both children with autism and in first-degree relatives. With functional magnetic resonance imaging, we found that the magnitude of RS to faces in neurotypical participants was negatively correlated with individual differences in autistic traits. We replicated this finding in a second experiment, while additional experiments showed that autistic traits also negatively predicted RS to images of scenes and simple geometric shapes. These findings suggest that a core aspect of neural function--the brain's response to repetition--is modulated by autistic traits.

Different neural mechanisms within occipitotemporal cortex underlie repetition suppression across same and different-size faces.

Repetition suppression (RS) (or functional magnetic resonance imaging adaptation) refers to the reduction in blood oxygen level-dependent signal following repeated presentation of a stimulus. RS is frequently used to investigate the role of face-selective regions in human visual cortex and is commonly thought to be a "localized" effect, reflecting fatigue of a neuronal population representing a given stimulus. In contrast, predictive coding theories characterize RS as a consequence of "top-down" changes in between-region modulation. Differentiating between these accounts is crucial for the correct interpretation of RS effects in the face-processing network. Here, dynamic causal modeling revealed that different mechanisms underlie different forms of RS to faces in occipitotemporal cortex. For both familiar and unfamiliar faces, repetition of identical face images (same size) was associated with changes in "forward" connectivity between the occipital face area (OFA) and the fusiform face area (FFA) (OFA-to-FFA). In contrast, RS across image size was characterized by altered "backward" connectivity (FFA-to-OFA). In addition, evidence was higher for models in which information projected directly into both OFA and FFA, challenging the role of OFA as the input stage of the face-processing network. These findings suggest "size-invariant" RS to faces is a consequence of interactions between regions rather than being a localized effect.

Emotion and personality factors influence the neural response to emotional stimuli.

Lindquist et al. assess the neural evidence for locationist versus psychological construction accounts of human emotion. A wealth of experimental and clinical investigations show that individual differences in emotion and personality influence emotion processing. These factors may also influence the brain's response to emotional stimuli. A synthesis of the relevant neuroimaging data must therefore take these factors into consideration.

Explaining away repetition effects via predictive coding.

Abstract Gotts, Chow and Martin summarize Predictive Coding models in which repetition-related decreases in neural activity reflect an "Explaining Away" of stimulus-driven neural activity. Here we elaborate the subtleties of testing such models, particularly with fMRI.

Changes in "top-down" connectivity underlie repetition suppression in the ventral visual pathway.

Repetition of the same stimulus leads to a reduction in neural activity known as repetition suppression (RS). In functional magnetic resonance imaging (fMRI), RS is found for multiple object categories. One proposal is that RS reflects locally based "within-region" changes, such as neural fatigue. Thus, if a given region shows RS across changes in stimulus size or view, then it is inferred to hold size- or view-invariant representations. An alternative hypothesis characterizes RS as a consequence of "top-down" between-region modulation. Differentiating between these accounts is central to the correct interpretation of fMRI RS data. It is also unknown whether the same mechanisms underlie RS to identical stimuli and RS across changes in stimulus size or view. Using fMRI, we investigated RS within a body-sensitive network in human visual cortex comprising the extrastriate body area (EBA) and the fusiform body area (FBA). Both regions showed RS to identical images of the same body that was unaffected by changes in body size or view. Dynamic causal modeling demonstrated that changes in backward, top-down (FBA-to-EBA) effective connectivity play a critical role in RS. Furthermore, only repetition of the identical image showed additional changes in forward connectivity (EBA-to-FBA). These results suggest that RS is driven by changes in top-down modulation, whereas the contribution of "feedforward" changes in connectivity is dependent on the precise nature of the repetition. Our results challenge previous interpretations regarding the underlying nature of neural representations made using fMRI RS paradigms.

Autism spectrum traits in the typical population predict structure and function in the posterior superior temporal sulcus.

Autism spectrum disorders (ASDs) are typically characterized by impaired social interaction and communication, narrow interests, and repetitive behaviors. The heterogeneity in the severity of these characteristics across individuals with ASD has led some researchers to suggest that these disorders form a continuum which extends into the general, or "typical," population, and there is growing evidence that the extent to which typical adults display autistic traits, as measured using the autism-spectrum quotient (AQ), predicts performance on behavioral tasks that are impaired in ASD. Here, we show that variation in autism spectrum traits is related to cortical structure and function within the typical population. Voxel-based morphometry showed that increased AQ scores were associated with decreased white matter volume in the posterior superior temporal sulcus (pSTS), a region important in processing socially relevant stimuli and associated with structural and functional impairments in ASD. In addition, AQ was correlated with the extent of cortical deactivation of an adjacent area of pSTS during a Stroop task relative to rest, reflecting variation in resting state function. The results provide evidence that autism spectrum characteristics are reflected in neural structure and function across the typical (non-ASD) population.

Adaptation studies suggest interactive feedback shapes responses in occipitotemporal regions.

Abstract Downing and Peelen portray the EBA and FBA as a largely impenetrable system, passing on visual signals to other cortical areas where high-level information is extracted. They suggest that the influence of other regions on EBA and FBA is primarily limited to changes in attentional modulation. In the following commentary, this proposal is evaluated within the context of a predictive coding framework. Recent evidence is discussed indicating that fMRI-adaptation effects in occipitotemporal cortex, including EBA and FBA, are consistent with the influence of higher-level modulation, suggesting that responses in these regions are shaped through the interactive feedback of a hierarchical network.

"You talkin' to me?" Self-relevant auditory signals influence perception of gaze direction.

In humans, direct gaze typically signals a deliberate attempt to communicate with an observer. An auditory signal with similar signal value is calling someone's name. We investigated whether the presence of this personally relevant signal in the auditory modality would influence perception of another individual's gaze. Participants viewed neutral faces displaying different gaze deviations while hearing someone call their own name or the name of another person. Results were consistent with our predictions, as participants judged faces with a wider range of gaze deviations as looking directly at them when they simultaneously heard their own name. The influence of this personally relevant signal was present only at ambiguous gaze deviations; thus, an overall response bias to categorize gaze as direct when hearing one's own name cannot account for the results. This study provides the first evidence that communicative intent signaled via the auditory modality influences the perception of another individual's gaze.

The Interaction Between Gaze and Facial Expression in the Amygdala and Extended Amygdala is Modulated by Anxiety.

Behavioral evidence indicates that angry faces are seen as more threatening, and elicit greater anxiety, when directed at the observer, whereas the influence of gaze on the processing of fearful faces is less consistent. Recent research has also found inconsistent effects of expression and gaze direction on the amygdala response to facial signals of threat. However, such studies have failed to consider the important influence of anxiety on the response to signals of threat; an influence that is well established in behavioral research and recent neuroimaging studies. Here, we investigated the way in which individual differences in anxiety would influence the interactive effect of gaze and expression on the response to angry and fearful faces in the human extended amygdala. Participants viewed images of fearful, angry and neutral faces, either displaying an averted or direct gaze. We found that state anxiety predicted an increased response in the dorsal amygdala/substantia innominata (SI) to angry faces when gazing at, relative to away from the observer. By contrast, high state anxious individuals showed an increased amygdala response to fearful faces that was less dependent on gaze. In addition, the relationship between state anxiety and gaze on emotional intensity ratings mirrored the relationship between anxiety and the amygdala/SI response. These results have implications for understanding the functional role of the amygdala and extended amygdala in processing signals of threat, and are consistent with the proposed role of this region in coding the relevance or significance of a stimulus to the observer.

Leaving a bad taste in your mouth but not in my insula.

Previous research has implicated regions of anterior insula/frontal operculum in processing conspecific facial expressions of disgust. It has been suggested however that there are a variety of disgust facial expression components which relate to the disgust-eliciting stimulus. The nose wrinkle is predominantly associated with irritating or offensive smells, the mouth gape and tongue extrusion with distaste and oral irritation, while a broader range of disgust elicitors including aversive interpersonal contacts and certain moral offenses are associated primarily with the upper lip curl. Using functional magnetic resonance imaging, we show that activity in the anterior insula/frontal operculum is seen only in response to canonical disgust faces, exhibiting the nose wrinkle and upper lip curl, and not in response to distaste facial expressions, exhibiting a mouth gape and tongue protrusion. Canonical disgust expressions also result in activity in brain regions linked to social cognition more broadly, including dorsal medial prefrontal cortex, posterior cingulate cortex, temporo-parietal junction and superior temporal sulcus. We interpret these differences in relation to the relative functional and communicative roles of the different disgust expressions and suggest a significant role for appraisal processes in the insula activation to facial expressions of disgust.

The amygdala response to images with impact.

Effective photojournalism provokes an emotional reaction and leaves a lasting impression upon the viewer. Striking and memorable images are often said to possess 'impact'. Within cognitive neuroscience memorable emotional images evoke a greater amygdala response. Research to date has focused on arousal as a causative factor, while the contribution of appraisal dimensions relating to salience of an item, goal relevance, or impact are yet to be addressed. We explored how differences in ratings of impact influenced amygdala activity to negative emotional images matched for valence, arousal and other factors. Increased amygdala activation was found to high impact when compared to neutral images, or high impact when compared to low impact images (matched for arousal). Our findings demonstrate that the amygdala response to emotional stimuli is not a function of arousal (or valence) alone and accord more with the proposal that the amygdala responds to the significance or relevance of an event.

Personality predicts the brain's response to viewing appetizing foods: the neural basis of a risk factor for overeating.

Eating is not only triggered by hunger but also by the sight of foods. Viewing appetizing foods alone can induce food craving and eating, although there is considerable variation in this "external food sensitivity" (EFS). Because increased EFS is associated with overeating, identifying its neural correlates is important for understanding the current epidemic of obesity. Animal research has identified the ventral striatum, amygdala, hypothalamus, medial prefrontal and premotor cortices as key interacting structures for feeding. However, it is unclear whether a similar network exists in humans and how it is affected by EFS. Using functional magnetic resonance imaging, we showed that viewing appetizing compared with bland foods produced changes in connectivity among the human ventral striatum, amygdala, anterior cingulate and premotor cortex that were strongly correlated with EFS. Differences in the dynamic interactions within the human appetitive network in response to pictures of appetizing foods may determine an individual's risk of obesity.