Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome.

How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14-24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial- and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence.

Ventral premotor-motor cortex interactions in the macaque monkey during grasp: response of single neurons to intracortical microstimulation.

Recent stimulation studies in monkeys and humans have shown strong interactions between ventral premotor cortex (area F5) and the hand area of primary motor cortex (M1). These short-latency interactions usually involve facilitation from F5 of M1 outputs to hand muscles, although suppression has also been reported. This study, performed in three awake macaque monkeys, sought evidence that these interactions could be mediated by short-latency excitatory and inhibitory responses of single M1 neurons active during grasping tasks. We recorded responses of these M1 neurons to single low-threshold (≤40 µA) intracortical microstimuli delivered to F5 sites at which grasp-related neurons were recorded. In 29 sessions, we tested 232 M1 neurons with stimuli delivered to between one and four sites in F5. Of the 415 responses recorded, 142 (34%) showed significant effects. The most common type of response was pure excitation (53% of responses), with short latency (1.8-3.0 ms) and brief duration (∼1 ms); purely inhibitory responses had slightly longer latencies (2-5 ms) and were of small amplitude and longer duration (5-7 ms). They accounted for 13% of responses, whereas mixed excitation then inhibition was seen in 34%. Remarkably, a rather similar set of findings applied to 280 responses of 138 F5 neurons to M1 stimulation; 109 (34%) responses showed significant effects. Thus, with low-intensity stimuli, the dominant interaction between these two cortical areas is one of short-latency, brief excitation, most likely mediated by reciprocal F5-M1 connections. Some neurons were tested with stimuli at both 20 and 40 µA; inhibition tended to dominate at the higher intensity.

How do the prevalence and relative risk of non-suicidal self-injury and suicidal thoughts vary across the population distribution of common mental distress (the p factor)? Observational analyses replicated in two independent UK cohorts of young people.

OBJECTIVES: To inform suicide prevention policies and responses to youths at risk by investigating whether suicide risk is predicted by a summary measure of common mental distress (CMD (the p factor)) as well as by conventional psychopathological domains; to define the distribution of suicide risks over the population range of CMD; to test whether such distress mediates the medium-term persistence of suicide risks. DESIGN: Two independent population-based cohorts. SETTING: Population based in two UK centres. PARTICIPANTS: Volunteers aged 14-24 years recruited from primary healthcare registers, schools and colleges, with advertisements to complete quotas in age-sex-strata. Cohort 1 is the Neuroscience in Psychiatry Network (n=2403); cohort 2 is the ROOTS sample (n=1074). PRIMARY OUTCOME MEASURES: Suicidal thoughts (ST) and non-suicidal self-injury (NSSI). RESULTS: We calculated a CMD score using confirmatory bifactor analysis and then used logistic regressions to determine adjusted associations between risks and CMD; curve fitting was used to examine the relative prevalence of STs and NSSI over the population distribution of CMD. We found a dose-response relationship between levels of CMD and risk of suicide. The majority of all subjects experiencing ST and NSSI (78% and 76% in cohort 1, and 66% and 71% in cohort 2) had CMD scores no more than 2 SDs above the population mean; higher scores indicated the highest risk but were, by definition, infrequent. Pathway mediation models showed that CMD mediated the longitudinal course of both ST and NSSI. CONCLUSIONS: NSSI and ST in youths reflect CMD that also mediates their persistence. Universal prevention strategies reducing levels of CMD in the whole population without recourse to screening or measurement may prevent more suicides than approaches targeting youths with the most severe distress or with psychiatric disorders.

Multiple Holdouts With Stability: Improving the Generalizability of Machine Learning Analyses of Brain-Behavior Relationships.

BACKGROUND: In 2009, the National Institute of Mental Health launched the Research Domain Criteria, an attempt to move beyond diagnostic categories and ground psychiatry within neurobiological constructs that combine different levels of measures (e.g., brain imaging and behavior). Statistical methods that can integrate such multimodal data, however, are often vulnerable to overfitting, poor generalization, and difficulties in interpreting the results. METHODS: We propose an innovative machine learning framework combining multiple holdouts and a stability criterion with regularized multivariate techniques, such as sparse partial least squares and kernel canonical correlation analysis, for identifying hidden dimensions of cross-modality relationships. To illustrate the approach, we investigated structural brain-behavior associations in an extensively phenotyped developmental sample of 345 participants (312 healthy and 33 with clinical depression). The brain data consisted of whole-brain voxel-based gray matter volumes, and the behavioral data included item-level self-report questionnaires and IQ and demographic measures. RESULTS: Both sparse partial least squares and kernel canonical correlation analysis captured two hidden dimensions of brain-behavior relationships: one related to age and drinking and the other one related to depression. The applied machine learning framework indicates that these results are stable and generalize well to new data. Indeed, the identified brain-behavior associations are in agreement with previous findings in the literature concerning age, alcohol use, and depression-related changes in brain volume. CONCLUSIONS: Multivariate techniques (such as sparse partial least squares and kernel canonical correlation analysis) embedded in our novel framework are promising tools to link behavior and/or symptoms to neurobiology and thus have great potential to contribute to a biologically grounded definition of psychiatric disorders.

Modulation of primary motor cortex outputs from ventral premotor cortex during visually guided grasp in the macaque monkey.

Area F5, in the ventral premotor cortex of the macaque monkey, plays a critical role in determining the hand shape appropriate for grasp of a visible object. F5 neurones show increased firing for particular types of grasp, and inactivation of F5 produces deficits in visually guided grasp. But how is F5 activity transformed into the appropriate pattern of hand muscle activity for efficient grasp? Here we investigate the pathways that may be involved by testing the effect of single stimuli delivered through microwires chronically implanted in area F5 and in primary motor cortex (M1) of two macaque monkeys. The EMG responses from M1 test (T) stimulation were recorded from 4-11 contralateral hand, digit and arm muscles during reach-to-grasp of visually presented objects. Conditioning (C) stimulation of F5, at intensities subthreshold for motor effects, caused strong modulation (over twofold) of M1 test (T) responses. The pattern of facilitation was specific. First, facilitation of the T response was particularly evident at short C-T intervals of -1 to 1 ms. Second, this facilitation was only present in some muscles and during reach-to-grasp of a subset of objects; it did not appear to be simply related to the level of EMG activity in the muscles at the moment of cortical stimulation or indeed to the upcoming contribution of that muscle during grasp. At later C-T intervals (1-6 ms), F5 stimulation caused significant suppression of the test M1 response. The results are in keeping with the concept that during visually guided grasp, F5 modulates corticospinal outputs from M1 in a muscle- and grasp-specific manner.

On-line control of grasping actions: object-specific motor facilitation requires sustained visual input.

Dorsal stream visual processing is generally considered to underlie visually driven action, but when subjects grasp an object from memory, as visual information is not available, ventral stream characteristics emerge. In this study we use paired-pulse transcranial magnetic stimulation (TMS) to investigate the importance of the current visual input during visuomotor grasp. Previously, the amplitude of the paired-pulse motor evoked potentials (MEPs) in hand muscles before movement onset have been shown to predict the subsequent pattern of muscle activity during grasp. Specific facilitation of paired-pulse MEPs may reflect premotor-motor (PMC-M1) cortex connectivity. Here we investigate the paired-pulse MEPs evoked under memory-cued and visually driven conditions before grasping one of two possible target objects (a handle or a disc). All trials began with a delay period of 1200 ms. Then, a TMS pulse served as the cue to reach, grasp and hold the target object for 0.5 s. Total trial length was 5 s. Both objects were continually visible in both conditions, but the way in which the target object was designated differed between conditions. In the memory-cued condition, the target object was illuminated for the first 200 ms of the trial only. In the visually driven condition, the target object was illuminated throughout the 5 s trial. Thus, the conditions differed in whether or not the object to be grasped was designated at the time of movement initiation. We found that the pattern of paired-pulse MEP facilitation matched the pattern of object-specific muscle activity only for the visually driven condition. The results suggest that PMC-M1 connectivity contributes to action selection only when immediate sensory information specifies which action to make.

Neural activity and fundamental learning, motivated by monetary loss and reward, are intact in mild to moderate major depressive disorder.

INTRODUCTION: Reduced motivation is an important symptom of major depression, thought to impair recovery by reducing opportunities for rewarding experiences. We characterized motivation for monetary outcomes in depressed outpatients (N = 39, 22 female) and controls (N = 22, 11 female) in terms of their effectiveness in seeking rewards and avoiding losses. We assessed motivational function during learning of associations between stimuli and actions, as well as when learning was complete. We compared the activity within neural circuits underpinning these behaviors between depressed patients and controls. METHODS: We used a Go/No-Go task that assessed subjects' abilities in learning to emit or withhold actions to obtain monetary rewards or avoid losses. We derived motivation-relevant parameters of behavior (learning rate, Pavlovian bias, and motivational influence of gains and losses). After learning, participants performed the task during functional magnetic resonance imaging (fMRI). We compared neural activation during anticipation of action emission vs. action inhibition, and for actions performed to obtain rewards compared to actions that avoid losses. RESULTS: Depressed patients showed a similar Pavlovian bias to controls and were equivalent in terms of withholding action to gain rewards and emitting action to avoid losses, behaviors that conflict with well-described Pavlovian tendencies to approach rewards and avoid losses. Patients were not impaired in overall performance or learning and showed no abnormal neural responses, for example in bilateral midbrain or striatum. We conclude that basic mechanisms subserving motivated learning are thus intact in moderate depression. IMPLICATIONS: Therapeutically, the intact mechanisms identified here suggest that learning-based interventions may be particularly effective in encouraging recovery. Etiologically, our results suggest that the severe motivational deficits clinically observed in depression are likely to have complex origins, possibly related to an impairment in the representation of future states necessary for long-term planning.

Vigour in active avoidance.

It would be maladaptive to learn about catastrophes by trial and error alone. Investment in planning and effort are necessary. Devoting too many resources to averting disaster, however, can impair quality of life, as in anxiety and paranoia. Here, we developed a novel task to explore how people adjust effort expenditure (vigor) so as to avoid negative consequences. Our novel paradigm is immersive, enabling us to measure vigor in the context of (simulated) disaster. We found that participants (N = 118) exerted effort to avoid disaster-associated states, adjusting their effort expenditure according to the baseline probability of catastrophe, in agreement with theoretical predictions. Furthermore, negative subjective emotional states were associated both with threat level and with increasing vigor in the face of disaster. We describe for the first time effort expenditure in the context of irreversible losses, with important implications for disorders marked by excessive avoidance.

Association of Neural and Emotional Impacts of Reward Prediction Errors With Major Depression.

Importance: Major depressive disorder (MDD) is associated with deficits in representing reward prediction errors (RPEs), which are the difference between experienced and predicted reward. Reward prediction errors underlie learning of values in reinforcement learning models, are represented by phasic dopamine release, and are known to affect momentary mood. Objective: To combine functional neuroimaging, computational modeling, and smartphone-based large-scale data collection to test, in the absence of learning-related concerns, the hypothesis that depression attenuates the impact of RPEs. Design, Setting, and Participants: Functional magnetic resonance imaging (fMRI) data were collected on 32 individuals with moderate MDD and 20 control participants who performed a probabilistic reward task. A risky decision task with repeated happiness ratings as a measure of momentary mood was also tested in the laboratory in 74 participants and with a smartphone-based platform in 1833 participants. The study was conducted from November 20, 2012, to February 17, 2015. Main Outcomes and Measures: Blood oxygen level-dependent activity was measured in ventral striatum, a dopamine target area known to represent RPEs. Momentary mood was measured during risky decision making. Results: Of the 52 fMRI participants (mean [SD] age, 34.0 [9.1] years), 30 (58%) were women and 32 had MDD. Of the 74 participants in the laboratory risky decision task (mean age, 34.2 [10.3] years), 44 (59%) were women and 54 had MDD. Of the smartphone group, 543 (30%) had a depression history and 1290 (70%) had no depression history; 918 (50%) were women, and 593 (32%) were younger than 30 years. Contrary to previous results in reinforcement learning tasks, individuals with moderate depression showed intact RPE signals in ventral striatum (z = 3.16; P = .002) that did not differ significantly from controls (z = 0.91; P = .36). Symptom severity correlated with baseline mood parameters in laboratory (ρ = -0.54; P < 1 × 10-6) and smartphone (ρ = -0.30; P < 1 × 10-39) data. However, participants with depression showed an intact association between RPEs and happiness in a computational model of momentary mood dynamics (z = 4.55; P < .001) that was not attenuated compared with controls (z = -0.42; P = .67). Conclusions and Relevance: The neural and emotional impact of RPEs is intact in major depression. These results suggest that depression does not affect the expression of dopaminergic RPEs and that attenuated RPEs in previous reports may reflect downstream effects more closely related to aberrant behavior. The correlation between symptom severity and baseline mood parameters supports an association between depression and momentary mood fluctuations during cognitive tasks. These results demonstrate a potential for smartphones in large-scale computational phenotyping, which is a goal for computational psychiatry.

Covert manual response preparation triggers attentional shifts: ERP evidence for the premotor theory of attention.

The premotor theory of attention claims that the preparation of goal-directed action and shifts of attention are closely linked, because they are controlled by shared sensorymotor mechanisms. Until now, support for this theory has come primarily from studies demonstrating links between saccade programming and attention shifts. The present event-related brain potential (ERP) study demonstrated that attentional orienting processes are also elicited during the covert preparation of unimanual responses. ERPs were recorded in the interval between a visual response-hand selection cue and a subsequent visual Go/Nogo signal when participants prepared to lift their left or right index finger. Lateralised ERP components elicited during response preparation were very similar to components previously observed during instructed endogenous attention shifts, indicating that analogous attentional orienting processes are activated in both cases. Somatosensory ERP components (P90, N140) were enhanced when task-irrelevant tactile probes were delivered during response preparation to the hand involved in an anticipated response, even when probes were presented well in advance of response execution. These results suggest that attentional shifts are triggered during unimanual response preparation, as predicted by the premotor theory. This link between manual response programming and attention is consistent with the hypothesis that common mechanisms are involved in the control of attention and action.

External Validation and Recalibration of Risk Prediction Models for Acute Traumatic Brain Injury among Critically Ill Adult Patients in the United Kingdom.

This study validates risk prediction models for acute traumatic brain injury (TBI) in critical care units in the United Kingdom and recalibrates the models to this population. The Risk Adjustment In Neurocritical care (RAIN) Study was a prospective, observational cohort study in 67 adult critical care units. Adult patients admitted to critical care following acute TBI with a last pre-sedation Glasgow Coma Scale score of less than 15 were recruited. The primary outcomes were mortality and unfavorable outcome (death or severe disability, assessed using the Extended Glasgow Outcome Scale) at six months following TBI. Of 3626 critical care unit admissions, 2975 were analyzed. Following imputation of missing outcomes, mortality at six months was 25.7% and unfavorable outcome 57.4%. Ten risk prediction models were validated from Hukkelhoven and colleagues, the Medical Research Council (MRC) Corticosteroid Randomisation After Significant Head Injury (CRASH) Trial Collaborators, and the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) group. The model with the best discrimination was the IMPACT "Lab" model (C index, 0.779 for mortality and 0.713 for unfavorable outcome). This model was well calibrated for mortality at six months but substantially under-predicted the risk of unfavorable outcome. Recalibration of the models resulted in small improvements in discrimination and excellent calibration for all models. The risk prediction models demonstrated sufficient statistical performance to support their use in research and audit but fell below the level required to guide individual patient decision-making. The published models for unfavorable outcome at six months had poor calibration in the UK critical care setting and the models recalibrated to this setting should be used in future research.

Excitability of human motor cortex inputs prior to grasp.

Transcranial magnetic stimulation (TMS) was used to investigate corticospinal excitability during the preparation period preceding visually guided self-paced grasping. Previously we have shown that while subjects prepare to grasp a visible object, paired-pulse TMS at a specific interval facilitates motor-evoked potentials (MEPs) in hand muscles in a manner that varies with the role of the muscle in shaping the hand for the upcoming grasp. This anticipatory modulation may reflect transmission of inputs to human primary motor cortex (M1) for visuomotor guidance of hand shape. Conversely, single-pulse TMS is known to suppress MEPs during movement preparation. Here we investigate the time course of single- and paired-pulse MEP modulation. TMS was delivered over M1, at different time intervals after visual presentation of either a handle or a disc to healthy subjects. Participants were instructed to view the object, and later to grasp it when given a cue. During grasp there was a specific pattern of hand muscle activity according to the object grasped. MEPs were evoked in these muscles by TMS delivered prior to grasp. Paired-pulse MEPs were facilitated, whilst single-pulse MEPs were suppressed. The pattern of facilitation matched the object-specific pattern of muscle activity for TMS pulses delivered 150 ms or more after object presentation. However, this effect was not present when TMS was delivered immediately after object presentation, or if the delivery of TMS was given separately from the cue to perform the grasp action. These results suggest that object-related information for preparation of appropriate hand shapes reaches M1 only immediately preceding execution of the grasp.

Having a body versus moving your body: How agency structures body-ownership.

We investigated how motor agency in the voluntary control of body movement influences body awareness. In the Rubber Hand Illusion (RHI), synchronous tactile stimulation of a rubber hand and the participant's hand leads to a feeling of the rubber hand being incorporated in the participant's own body. One quantifiable behavioural correlate of the illusion is an induced shift in the perceived location of the participant's hand towards the rubber hand. Previous studies showed that the induced changes in body awareness are local and fragmented: the proprioceptive drift is largely restricted to the stimulated finger. In the present study, we investigated whether active and passive movements, rather than tactile stimulation, would lead to similarly fragmented body awareness. Participants watched a projected image of their hand under three conditions: active finger movement, passive finger movement, and tactile stimulation. Visual feedback was either synchronous or asynchronous with respect to stimulation of the hand. A significant overall RHI, defined as greater drifts following synchronous than asynchronous stimulation, was found in all cases. However, the distribution of the RHI across stimulated and non-stimulated fingers depended on the kind of stimulation. Localised proprioceptive drifts, specific to the stimulated finger, were found for tactile and passive stimulation. Conversely, during active movement of a single digit, the proprioceptive drifts were not localised to that digit, but were spread across the whole hand. Whereas a purely proprioceptive sense of body-ownership is local and fragmented, the motor sense of agency integrates distinct body-parts into a coherent, unified awareness of the body.