Multi-level prediction of substance use: Interaction of white matter integrity, resting-state connectivity and inhibitory control measured repeatedly in every-day life.

Substance use disorders are characterized by inhibition deficits related to disrupted connectivity in white matter pathways, leading via interaction to difficulties in resisting substance use. By combining neuroimaging with smartphone-based ecological momentary assessment (EMA), we questioned how biomarkers moderate inhibition deficits to predict use. Thus, we aimed to assess white matter integrity interaction with everyday inhibition deficits and related resting-state network connectivity to identify multi-dimensional predictors of substance use. Thirty-eight patients treated for alcohol, cannabis or tobacco use disorder completed 1 week of EMA to report substance use five times and complete Stroop inhibition testing twice daily. Before EMA tracking, participants underwent resting state functional MRI and diffusion tensor imaging (DTI) scanning. Regression analyses were conducted between mean Stroop performances and whole-brain fractional anisotropy (FA) in white matter. Moderation testing was conducted between mean FA within significant clusters as moderator and the link between momentary Stroop performance and use as outcome. Predictions between FA and resting-state connectivity strength in known inhibition-related networks were assessed using mixed modelling. Higher FA values in the anterior corpus callosum and bilateral anterior corona radiata predicted higher mean Stroop performance during the EMA week and stronger functional connectivity in occipital-frontal-cerebellar regions. Integrity in these regions moderated the link between inhibitory control and substance use, whereby stronger inhibition was predictive of the lowest probability of use for the highest FA values. In conclusion, compromised white matter structural integrity in anterior brain systems appears to underlie impairment in inhibitory control functional networks and compromised ability to refrain from substance use.

Interindividual Brain and Behavior Differences in Adaptation to Unexpected Uncertainty.

To adapt to a new environment, individuals must alternate between exploiting previously learned "action-consequence" combinations and exploring new actions for which the consequences are unknown: they face an exploration/exploitation trade-off. The neural substrates of these behaviors and the factors that may relate to the interindividual variability in their expression remain overlooked, in particular when considering neural connectivity patterns. Here, to trigger environmental uncertainty, false feedbacks were introduced in the second phase of an associative learning task. Indices reflecting exploitation and cost of uncertainty were computed. Changes in the intrinsic connectivity were determined using resting-state functional connectivity (rFC) analyses before and after performing the "cheated" phase of the task in the MRI. We explored their links with behavioral and psychological factors. Dispersion in the participants' cost of uncertainty was used to categorize two groups. These groups showed different patterns of rFC changes. Moreover, in the overall sample, exploitation was correlated with rFC changes between (1) the anterior cingulate cortex and the cerebellum region 3, and (2) the left frontal inferior gyrus (orbital part) and the right frontal inferior gyrus (triangular part). Anxiety and doubt about action propensity were weakly correlated with some rFC changes. These results demonstrate that the exploration/exploitation trade-off involves the modulation of cortico-cerebellar intrinsic connectivity.

Conscious awareness of others' actions during observational learning does not benefit motor skill performance.

The conscious awareness of motor success during motor learning has recently been revealed as a learning factor. In these studies, participants had to learn a motor sequence and to detect when they assumed the execution had reached a maximal fluidity. The consciousness groups showed better motor performance during a delayed post-training test than the non-consciousness control groups. Based on the "similar mechanism" hypothesis between observational and physical practice, we tested this beneficial effect of the conscious awareness of action in an observational learning context. In the present study, two groups learned a motor sequence task by observing a videotaped human model performing the task. However, only the consciousness group had to detect the maximal fluidity of the learning human model during observational practice. Unpredictably, no difference was detected between groups during the post-training test. However, the consciousness group outperformed the non-consciousness control group for tests that assessed the motor knowledges.

Caudate gray matter volumes and risk of relapse in Type A alcohol-dependent patients: A 7-year MRI follow-up study.

Background: Whether alteration in regional brain volumes can be detected in Type A alcoholics both at baseline and after a long follow-up remains to be confirmed. Therefore, we examined volume alterations at baseline, and longitudinal changes in a small follow-up subsample. Methods: In total of 26 patients and 24 healthy controls were assessed at baseline using magnetic resonance imaging and voxel-based morphometry, among which 17 patients and 6 controls were re-evaluated 7 years later. At baseline, regional cerebral volumes of patients were compared to controls. At follow-up, three groups were compared: abstainers (n = 11, more than 2 years of abstinence), relapsers (n = 6, <2 years of abstinence), and controls (n = 6). Results: The cross-sectional analyses detected, at both times, higher caudate nuclei volumes bilaterally in relapsers compared to abstainers. In abstainers, the longitudinal analysis indicated recovery of normal gray matter volumes in the middle and inferior frontal gyrus, and in the middle cingulate, while white matter volumes recovery was detected in the corpus callosum and in anterior and superior white matter specific regions. Conclusions: Overall, the present investigation revealed larger caudate nuclei in the relapser AUD patient group both at baseline and at follow-up in the cross-sectional analyses. This finding suggest that a higher caudate volume could be a candidate risk factor of relapse. In patients with specific type A alcohol-dependence, we showed that long-term recovery in fronto-striato-limbic GM and WM volumes occurs during long-term abstinence. These results support the crucial role of frontal circuitry in AUD.

Neural fatigue by passive induction: repeated stimulus exposure results in cognitive fatigue and altered representations in task-relevant networks.

Cognitive fatigue is defined by a reduced capacity to perform mental tasks. Despite its pervasiveness, the underlying neural mechanisms remain elusive. Specifically, it is unclear whether prolonged effort affects performance through alterations in over-worked task-relevant neuronal assemblies. Our paradigm based on repeated passive visual stimulation discerns fatigue effects from the influence of motivation, skill and boredom. We induced performance loss and observed parallel alterations in the neural blueprint of the task, by mirroring behavioral performance with multivariate neuroimaging techniques (MVPA) that afford a subject-specific approach. Crucially, functional areas that responded the most to repeated stimulation were also the most affected. Finally, univariate analysis revealed clusters displaying significant disruption within the extrastriate visual cortex. In sum, here we show that repeated stimulation impacts the implicated brain areas' activity and causes tangible behavioral repercussions, providing evidence that cognitive fatigue can result from local, functional, disruptions in the neural signal induced by protracted recruitment.

Mood Variability, Craving, and Substance Use Disorders: From Intrinsic Brain Network Connectivity to Daily Life Experience.

BACKGROUND: Substance use disorders (SUDs) are major contributors to morbidity and mortality rates worldwide, and this global burden is attributable in large part to the chronic nature of these conditions. Increased mood variability might represent a form of emotional dysregulation that may have particular significance for the risk of relapse in SUD, independent of mood severity or diagnostic status. However, the neural biomarkers that underlie mood variability remain poorly understood. METHODS: Ecological momentary assessment was used to assess mood variability, craving, and substance use in real time in 54 patients treated for addiction to alcohol, cannabis, or nicotine and 30 healthy control subjects. Such data were jointly examined relative to spectral dynamic causal modeling of effective brain connectivity within 4 networks involved in emotion generation and regulation. RESULTS: Differences in effective connectivity were related to daily life variability of emotional states experienced by persons with SUD, and mood variability was associated with craving intensity. Relative to the control participants, effective connectivity was decreased for patients in the prefrontal control networks and increased in the emotion generation networks. Findings revealed that effective connectivity within the patient group was modulated by mood variability. CONCLUSIONS: The intrinsic causal dynamics in large-scale neural networks underlying emotion regulation play a predictive role in a patient's susceptibility to experiencing mood variability (and, subsequently, craving) in daily life. The findings represent an important step toward informing interventional research through biomarkers of factors that increase the risk of relapse in persons with SUD.

Craving dynamics and related cerebral substrates predict timing of use in alcohol, tobacco, and cannabis use disorders.

Background: Patients treated for Substance Use Disorders exhibit highly fluctuating patterns of craving that could reveal novel prognostic markers of use. Accordingly, we 1) measured fluctuations within intensively repeated measures of craving and 2) linked fluctuations of craving to connectivity indices within resting-state (rs) brain regions to assess their relation to use among patients undergoing treatment for Alcohol, Tobacco and Cannabis Use Disorders. Method: Participants -64 individuals with SUD for tobacco, alcohol, or cannabis and 35 healthy controls-completed a week of Ecological Momentary Assessment (EMA) during which they reported craving intensity and substance use five times daily. Before EMA, a subsample of 50 patients, and 34 healthy controls also completed resting-state (rs)-MRI acquisitions. Craving temporal dynamics within each day were characterized using Standard Deviation (SD), Auto-Correlation Factor (ACF), and Mean Successive Square Difference (MSSD). Absolute Difference (AD) in craving between assessments was a prospective prediction measure. Results: Within-day, higher MSSD predicted greater substance use while controlling for mean craving. Prospectively higher AD predicted later increased substance use independently of previous use or craving level. Moreover, MSSD was linked to strength in five functional neural connections, most involving frontotemporal systems. Cerebello-thalamic and thalamo-frontal connectivity were also linked to substance use and distinguished the SUD from the controls. Conclusion: To the best of our knowledge, this is the first study to indicate that instability in craving may be a trigger for use in several SUD types, beyond the known effect of craving intensity.

Impact of Metacognitive and Psychological Factors in Learning-Induced Plasticity of Resting State Networks.

While resting-state networks are able to rapidly adapt to experiences and stimuli, it is currently unknown whether metacognitive processes such as confidence in learning and psychological temperament may influence this process. We explore the neural traces of confidence in learning and their variability by: (1) targeting rs-networks in which functional connectivity (FC) modifications induced by a learning task were associated either with the participant's performance or confidence in learning; and (2) investigating the links between FC changes and psychological temperament. Thirty healthy individuals underwent neuropsychological and psychometric evaluations as well as rs-fMRI scans before and after a visuomotor associative learning task. Confidence in learning was positively associated with the degree of FC changes in 11 connections including the cerebellar, frontal, parietal, and subcortical areas. Variability in FC changes was linked to the individual's level of anxiety sensitivity. The present findings indicate that reconfigurations of resting state networks linked to confidence in learning differ from those linked to learning accuracy. In addition, certain temperament characteristics appear to influence these reconfigurations.

Real-time cognitive performance and positive symptom expression in schizophrenia.

Deficits in cognitive functions are frequent in schizophrenia and are often conceptualized as stable characteristics of this disorder. However, cognitive capacities may fluctuate over the course of a day and it is unknown if such variation may be linked to the dynamic expression of psychotic symptoms. This investigation used Ecological Momentary Assessment (EMA) to provide mobile tests of cognitive functions and positive symptoms in real time. Thirty-three individuals with schizophrenia completed five EMA assessments per day for a one-week period that included real-time assessments of cognitive performance and psychotic symptoms. A subsample of patients and 31 healthy controls also completed a functional MRI examination. Relative to each individual's average score, moments of worsened cognitive performance on the mobile tests were associated with an increased probability of positive symptom occurrence over subsequent hours of the day (coef = 0.06, p < 0.05), adjusting for the presence of psychotic symptoms at the moment of mobile test administration. These prospective associations varied as a function of graph theory indices in MRI analyses. These findings demonstrate that cognitive performance is prospectively linked to psychotic symptom expression in daily life, and that underlying brain markers may be observed in the Executive Control Network. While the potential causal nature of this association remains to be investigated, our results offer promising prospects for a better understanding of the underlying mechanisms of symptom expression in schizophrenia.

Altered Cerebro-Cerebellar Dynamic Functional Connectivity in Alcohol Use Disorder: a Resting-State fMRI Study.

Alcohol use disorder (AUD) is widely associated with cerebellar dysfunction and altered cerebro-cerebellar functional connectivity (FC) that lead to cognitive impairments. Evidence for this association comes from resting-state functional magnetic resonance imaging (rsfMRI) studies that assess time-averaged measures of FC across the duration of a typical scan. This approach, however, precludes the assessment of potentially FC dynamics happening at faster timescales. In this study, using rsfMRI data, we aim at exploring cerebro-cerebellar FC dynamics in AUD patients (N = 18) and age- and sex-matched controls (N = 18). In particular, we quantified group-level differences in the temporal variability of FC between the posterior cerebellum and large-scale cognitive systems, and we investigated the role of the cerebellum in large-scale brain dynamics in terms of the temporal flexibility and integration of its regions. We found that, relative to controls, the AUD group exhibited significantly greater FC variability between the cerebellum and both the frontoparietal executive control (F1,31 = 7.01, p(FDR) = 0.028) and ventral attention (F1,31 = 7.35, p(FDR) = 0.028) networks. Moreover, the AUD group exhibited significantly less flexibility (F1,31 = 8.61, p(FDR) = 0.028) and greater integration (F1,31 = 9.11, p(FDR) = 0.028) in the cerebellum. Finally, in an exploratory analysis, we found distributed changes in the dynamics of canonical large-scale networks in AUD. Overall, this study brings evidence of AUD-related alterations in dynamic FC within major cerebro-cerebellar networks. This pattern has implications for explaining the development and maintenance of this disorder and improving our understating of the cerebellum's involvement in addiction.

Functional brain connectivity changes across the human life span: From fetal development to old age.

The dynamic of the temporal correlations between brain areas, called functional connectivity (FC), undergoes complex transformations through the life span. In this review, we aim to provide an overview of these changes in the nonpathological brain from fetal life to advanced age. After a brief description of the main methods, we propose that FC development can be divided into four main phases: first, before birth, a strong change in FC leads to the emergence of functional proto-networks, involving mainly within network short-range connections. Then, during the first years of life, there is a strong widespread organization of networks which starts with segregation processes followed by a continuous increase in integration. Thereafter, from adolescence to early adulthood, a refinement of existing networks in the brain occurs, characterized by an increase in integrative processes until about 40 years. Middle age constitutes a pivotal period associated with an inversion of the functional brain trajectories with a decrease in segregation process in conjunction to a large-scale reorganization of between network connections. Studies suggest that these processes are in line with the development of cognitive and sensory functions throughout life as well as their deterioration. During aging, results support the notion of dedifferentiation processes, which refer to the decrease in functional selectivity of the brain regions, resulting in more diffuse and less specialized FC, associated with the disruption of cognitive functions with age. The inversion of developmental processes during aging is in accordance with the developmental models of neuroanatomy for which the latest matured regions are the first to deteriorate.

Precision Preventive Medicine of Relapse in Smoking Cessation: Can MRI Inform the Search of Intermediate Phenotypes?

Chronic tobacco smoking remains a major health problem worldwide. Numerous smokers wish to quit but most fail, even if they are helped. The possibility of identifying neuro-biomarkers in smokers at high risk of relapse could be of incredible progress toward personalized prevention therapy. Our aim is to provide a scoping review of this research topic in the field of Magnetic Resonance Imaging (MRI) and to review the studies that investigated if MRI defined markers predicted smoking cessation treatment outcome (abstainers versus relapsers). Based on the available literature, a meta-analysis could not be conducted. We thus provide an overview of the results obtained and take stock of methodological issues that will need to be addressed to pave the way toward precision medicine. Based on the most consistent findings, we discuss the pivotal role of the insula in light of the most recent neurocognitive models of addiction.

Changes in resting-state functional brain connectivity associated with head impacts over one men's semi-professional soccer season.

Soccer, as a contact sport, exposes players to repetitive head impacts, especially through heading the ball. The question of a long-term brain cumulative effect remains. Our objective was to determine whether exposure to head impacts over one soccer season was associated with changes in functional brain connectivity at rest, using magnetic resonance imaging (MRI). In this prospective cohort study, 10 semi-professional men soccer players, aged 18-25 years, and 20 age-matched men athletes without a concussion history and who do not practice any contact sport were recruited in Bordeaux (France). Exposure to head impacts per soccer player during competitive games over one season was measured using video analysis. Resting-state functional magnetic resonance imaging data were acquired for both groups at two times, before and after the season. With a seed-based analysis, resting-state networks that have been intimately associated with aspects of cognitive functioning were investigated. The results showed a mean head impacts of 42 (±33) per soccer player over the season, mainly intentional head-to-ball impacts and no concussion. No head impact was found among the other athletes. The number of head impacts between the two MRI acquisitions before and after the season was associated with increased connectivity within the default mode network and the cortico-cerebellar network. In conclusion, our findings suggest that the brain functioning changes over one soccer season in association with exposure to repetitive head impacts.

Age-related change in episodic memory: role of functional and structural connectivity between the ventral posterior cingulate and the parietal cortex.

While the neural correlates of age-related episodic memory decline have been extensively studied, the precise involvement of the Posterior Cingulate Cortex (PCC) and posterior parietal cortex (the precuneus and the angular gyrus), remains unclear. The present study examined functional and structural neural correlates of age-related episodic memory change assessed over 12 years in 120 older adults (range 76-90 years). Episodic memory performance was measured using the Free and Cued Selective Reminding Test (FCSRT); functional connectivity metrics were computed from resting-state fMRI images and structural connectivity metrics were assessed through microstructural properties of reconstructed tract using a native space pipeline. We found that FCSRT change was significantly associated with the functional connectivity between the ventral PCC and three parietal regions, the ventral superior, the inferior part of the precuneus, and the rostro dorsal part of the angular gyrus. This association was independent of hippocampal volume. In addition, we found the that change in FCSRT scores was associated with fractional anisotropy of the tract connecting the ventral PCC and the ventral superior part of the precuneus. Change in episodic memory in aging was therefore related to a combination of high functional connectivity and low structural connectivity between the ventral PCC and the ventral superior part of the precuneus.

Static and dynamic aspects of cerebro-cerebellar functional connectivity are associated with self-reported measures of impulsivity: A resting-state fMRI study.

Human and animal brain studies bring converging evidence of a possible role for the cerebellum and the cerebro-cerebellar system in impulsivity. However, the precise nature of the relation between cerebro-cerebellar coupling and impulsivity is far from understood. Characterizing functional connectivity (FC) patterns between large-scale brain networks that mediate different forms of impulsivity, and the cerebellum may improve our understanding of this relation. Here, we analyzed static and dynamic features of cerebro-cerebellar FC using a highly sampled resting-state functional magnetic resonance imaging (rs-fMRI) dataset and tested their association with two widely used self-reports of impulsivity: the UPPS-P impulsive behavior scale and the behavioral inhibition/approach systems (BIS/BAS) in a large group of healthy subjects (N = 134, ≈ 1 hr of rs-fMRI/subject). We employed robust data-driven techniques to identify cerebral and cerebellar resting-state networks and extract descriptive summary measures of static and dynamic cerebro-cerebellar FC. We observed evidence linking BIS, BAS, sensation seeking, and lack of premeditation to the total strength and temporal variability of FC within networks connecting regions of the prefrontal cortex, precuneus, posterior cingulate cortex, basal ganglia, and thalamus with the cerebellum. Overall, our findings improve the existing knowledge of the neural correlates of impulsivity and the behavioral correlates of the cerebro-cerebellar system.

Learning-driven cerebellar intrinsic functional connectivity changes in men.

Learning involves distributed but coordinated activity among the widespread connected brain areas. Increase in areas connections' strength may be established offline, that is, aside from the task itself, in a resting-state. The resulting functional connectivity may hence constitute a neural trace of the learning episode. The present study examined whether a conditional visuomotor learning task previously shown to activate the cerebellum would modify cerebellar intrinsic connectivity in groups of young and older male subjects. In the group of young subjects, resting-state connectivity within several cerebellar networks (fronto-cerebellar, temporo-cerebellar, cerebello-cerebellar) was modified following the task. In most cases, modulation resulted in increased anticorrelations between cerebellar and cortical areas and the amplitude of changes was correlated with learning efficacy. The group of older subjects drastically differed, with sparser modifications of resting-state functional connectivity and no cerebellar networks involved. The findings of this exploratory study indicate that associative learning modifies the strength of intrinsic connectivity in young subjects but to a lesser degree in older subjects. They further suggest that functional connectivity within cerebellar networks may play an operative role in this kind of learning.

Altered default mode network connectivity in adolescents with post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is characterized by intrusions, re-experiencing, avoidance and hyperarousal. These symptoms might be linked to dysfunction in core neurocognitive networks subserving self-referential mental processing (default mode network, DMN), detection of salient stimuli (salience network, SN) and cognitive dysfunction (central executive network, CEN). Resting state studies in adolescent PTSD are scarce and findings are inconsistent, probably due to differences in patient symptom severity. Resting state brain activity was measured in 14 adolescents with severe PTSD and 24 age-matched controls. Seed-based connectivity analyses were used to examine connectivity between the DMN and the whole brain, including regions from other networks (SN and CEN). The relationships of network properties with symptom dimensions (severity, anxiety and depression) and episodic memory were also examined. Analyses revealed decreased within-DMN connectivity (between PCC and occipital cortex) in patients compared to controls. Furthermore, within-DMN connectivity (between PCC and hippocampus) correlated negatively with symptom dimensions (severity and anxiety), while increased connectivity (DMN-SN and DMN-CEN) correlated positively with episodic memory measures. These abnormal network properties found in adolescent PTSD corroborate those previously reported in adult PTSD. Decreased within-DMN connectivity and disrupted DMN-SN and DMN-CEN coupling could form the basis for intrusive trauma recollection and impaired episodic autobiographical recall in PTSD.

Neuropsychological Impairment in Detoxified Alcohol-Dependent Subjects with Preserved Psychosocial Functioning.

BACKGROUND: Chronic alcoholism and its related cognitive impairments are associated with increased social, relational, and professional deficits which have a variable overall impact on social integration. These impairments are known to have varying severities and have rarely been studied among healthy alcohol-dependent subjects with preserved psychosocial functioning. Thus, the objective of this study is to describe neuropsychological performance in this particular population. METHOD: Twenty-nine socially adjusted alcohol-dependent men, hospitalized for a first or second withdrawal and abstinent for 3 weeks minimum, were compared to 29 healthy non-alcoholic controls. All subjects underwent clinical and psychiatric examination, neuropsychological tests of memory (M), working memory (WM), and executive functions (EF). Comparisons were performed using Student's t-tests or Mann-Whitney U tests. RESULTS: No group differences were found on the Self-Reported Social Adjustment Scale (SAS-SR) or in the Mini-Mental State Examination. Compared to controls, patients had greater episodic, spatial, and WM deficits as well as slightly altered executive functions. In contrast, their executive functions (spontaneous flexibility, criteria generation, rule maintenance, and inhibitory control) were relatively preserved. CONCLUSION: Our sample of socially and professionally integrated alcoholic patients shows fewer cognitive deficits than described in previous studies. Our results suggest that early on, alcohol-dependent subjects develop compensatory adaptation processes to preserve social function and adaptation. Minor cognitive impairments should be screened early in the disease to integrate cognitive interventions into the health-care plan to thus eventually prevent further socio-professional marginalization.