The risk of cannabis use disorder is mediated by altered brain connectivity: A chronnectome study.

The brain mechanisms underlying the risk of cannabis use disorder (CUD) are poorly understood. Several studies have reported changes in functional connectivity (FC) in CUD, although none have focused on the study of time-varying patterns of FC. To fill this important gap of knowledge, 39 individuals at risk for CUD and 55 controls, stratified by their score on a self-screening questionnaire for cannabis-related problems (CUDIT-R), underwent resting-state functional magnetic resonance imaging. Dynamic functional connectivity (dFNC) was estimated using independent component analysis, sliding-time window correlations, cluster states and meta-state indices of global dynamics and were compared among groups. At-risk individuals stayed longer in a cluster state with higher within and reduced between network dFNC for the subcortical, sensory-motor, visual, cognitive-control and default-mode networks, relative to controls. More globally, at-risk individuals had a greater number of meta-states and transitions between them and a longer state span and total distance between meta-states in the state space. Our findings suggest that the risk of CUD is associated with an increased dynamic fluidity and dynamic range of FC. This may result in altered stability and engagement of the brain networks, which can ultimately translate into altered cortical and subcortical function conveying CUD risk. Identifying these changes in brain function can pave the way for early pharmacological and neurostimulation treatment of CUD, as much as they could facilitate the stratification of high-risk individuals.

Proteomic Analysis Reveals Potential Exosomal Biomarkers in Patients With Sporadic Alzheimer Disease.

BACKGROUND: Despite substantial progress made in the past decades, the pathogenesis of sporadic Alzheimer disease (sAD) and related biological markers of the disease are still controversially discussed. Cerebrospinal fluid and functional brain imaging markers have been established to support the clinical diagnosis of sAD. Yet, due to the invasiveness of such diagnostics, less burdensome markers have been increasingly investigated in the past years. Among such markers, extracellular vesicles may yield promise in (early) diagnostics and treatment monitoring in sAD. MATERIALS AND METHODS: In this pilot study, we collected the blood plasma of 18 patients with sAD and compared the proteome of extracted extracellular vesicles with the proteome of 11 age-matched healthy controls. The resulting proteomes were characterized by Gene Ontology terms and between-group statistics. RESULTS: Ten distinct proteins were found to significantly differ between sAD patients and controls (P<0.05, False Discovery Rate, corrected). These proteins included distinct immunoglobulins, fibronectin, and apolipoproteins. CONCLUSIONS: These findings lend further support for exosomal changes in neurodegenerative disorders, and particularly in sAD. Further proteomic research could decisively advance our knowledge of sAD pathophysiology as much as it could foster the development of clinically meaningful biomarkers.

Structure/function interrelationships and illness insight in patients with schizophrenia: a multimodal MRI data fusion study.

Illness insight in schizophrenia (SZ) has an important impact on treatment outcome, integration into society and can vary over the course of the disorder. To deal with and treat reduced or absent illness insight, we need to better understand its functional and structural correlates. Previous studies showed regionally abnormal brain volume in brain areas related to cognitive control and self-reference. However, little is known about associations between illness insight and structural and functional network strength in patients with SZ. This study employed a cross-sectional design to examine structural and functional differences between patients with SZ (n = 74) and healthy controls (n = 47) using structural and resting-state functional magnetic resonance imaging (MRI). Voxel-based morphometry was performed on structural data, and the amplitude of low frequency fluctuations (ALFF) was calculated for functional data. To investigate abnormal structure/function interrelationships and their association with illness insight, we used parallel independent component analysis (pICA). Significant group (SZ vs. HC) differences were detected in distinct structural and functional networks, predominantly comprising frontoparietal, temporal and cerebellar regions. Significant associations were found between illness insight and two distinct structural networks comprising frontoparietal (pre- and postcentral gyrus, inferior parietal lobule, thalamus, and precuneus) and posterior cortical regions (cuneus, precuneus, lingual, posterior cingulate, and middle occipital gyrus). Finally, we found a significant relationship between illness insight and functional network comprising temporal regions (superior temporal gyrus). This study suggests that aberrant structural and functional integrity of neural systems subserving cognitive control, memory and self-reference are tightly coupled to illness insight in SZ.

Functional correlates of neurological soft signs in heavy cannabis users.

Sensorimotor dysfunction has been previously reported in persons with cannabis dependence. Such individuals can exhibit increased levels of neurological soft signs (NSS), particularly involving motor coordination, sensorimotor integration and complex motor task performance. Abnormal NSS levels can also be detected in non-dependent individuals with heavy cannabis use (HCU), yet very little is known about the functional correlates underlying such deficits. Here, we used resting-state functional magnetic resonance imaging (MRI) to investigate associations between NSS and intrinsic neural activity (INA) in HCU (n = 21) and controls (n = 26). Compared with controls, individuals with HCU showed significantly higher NSS across all investigated subdomains. Three of these subdomains, that is, motor coordination, sensorimotor integration and complex motor task behaviour, were associated with specific use-dependent variables, particularly age of onset of cannabis use and current cannabis use. Between-group comparisons of INA revealed lower regional homogeneity (ReHo) in left precentral gyrus, left inferior occipital gyrus, right triangular pat of the inferior frontal gyrus and right precentral gyrus in HCU compared with controls. In addition, HCU showed also higher ReHo in right cerebellum and left postcentral gyrus compared with controls. Complex motor task behaviour in HCU was significantly related to INA in postcentral, inferior frontal and occipital cortices. Our findings indicate abnormal ReHo in HCU in regions associated with sensorimotor, executive control and visuomotor-integration processes. Importantly, we show associations between ReHo, cannabis-use behaviour and execution of complex motor tasks. Given convergent findings in manifest psychotic disorders, this study suggests an HCU endophenotype that may present with a cumulative risk for psychosis.

Neurochemical Correlates of Cue Reactivity in Individuals with Excessive Smartphone Use.

BACKGROUND: Excessive smartphone use (ESU), that is, a pattern of smartphone use that shows specific features of addictive behavior, has increasingly attracted societal and scientific interest in the past years. On the neurobiological level, ESU has recently been related to structural and functional variation in reward and salience processing networks, as shown by, for example, aberrant patterns of neural activity elicited by specific smartphone cues. OBJECTIVES: Expanding on these findings, using cross-modal correlations of magnetic resonance imaging (MRI)-based measures with nuclear imaging-derived estimates, we aimed at identifying neurochemical pathways that are related to ESU. METHODS: Cross-modal correlations between functional MRI data derived from a cue-reactivity task administered in persons with and without ESU and specific PET/SPECT receptor probability maps. RESULTS: The endogenous mu-opioid receptor (MOR) system was found to be significantly (FDR-corrected) correlated with fMRI data, and z-transformed correlation coefficients showed an association (albeit nonsignificant after FDR-correction) between MOR and the Smartphone Addiction Inventory "withdrawal" dimension. CONCLUSIONS: We could identify the MOR system as a neurochemical pathway associated with ESU. The MOR system is closely linked to the reward system, which has been recognized as a key player in addictive disorders. Together with its potential link to withdrawal, the MOR system hints toward a biologically highly relevant marker, which should be taken into consideration in the ongoing scientific discussion on technology-related addictive behaviors.

Effects of Mindfulness-Based Interventions on Gray Matter Volume in Patients with Opioid Dependence.

INTRODUCTION: Recently, several mindfulness-based programs showed promising clinical effects in the treatment of psychiatric disorders including substance use disorders. However, very little is known about the effects of mindfulness-based interventions (MBIs) on brain structure in such patients. METHODS: This study aimed to detect changes in gray matter volume (GMV) in opioid-dependent patients receiving MBI during their first month of treatment. Thirty patients were assigned to either 3 weeks of MBI (n = 16) or treatment as usual (TAU, n = 14) and were investigated using structural magnetic resonance imaging before and after treatment. Longitudinal pipeline of the Computational Anatomy Toolbox for SPM (CAT12) was used to detect significant treatment-related changes over time. The identified GMV changes following treatment were related to clinically relevant measures such as impulsivity, distress tolerance, and mindfulness. RESULTS: After treatment, increased mindfulness scores were found in individuals receiving MBI compared to TAU. In the MBI group, there were also significant differences with respect to distress tolerance and impulsivity. Effects on mindfulness, distress tolerance, and impulsivity were also found in the TAU group. Longitudinal within-group analysis revealed increased left anterior insula GMV in individuals receiving MBI. Anterior insula volume increase was associated with decreased impulsivity levels. In the TAU group, significant GMV changes were found in the right lingual gyrus and right entorhinal cortex. DISCUSSION/CONCLUSION: MBI can yield significant clinical effects during early abstinence from opioid dependence. MBI is particularly associated with increased insula GMV, supporting an important role of this region in the context of MBI-induced neural changes.

Cortical morphology and illness insight in patients with schizophrenia.

Insight into illness in schizophrenia (SZ) patients has a major impact on treatment adherence and outcome. Previous studies have linked distinct deviations of brain structure to illness insight, specifically in frontoparietal and subcortical regions. Some of these abnormalities are thought to reflect aberrant cortical development. In this study, we used cross-sectional data to examine associations between illness insight and two cortical surface markers that are known to follow distinct neurodevelopmental trajectories, i.e. cortical gyrification (CG) and thickness (CT). CG and CT was investigated in SZ patients (n = 82) and healthy controls (HC, n = 48) using 3 T structural magnetic resonance imaging. Illness insight in SZ patients was measured using the OSSTI scale, an instrument that provides information on two distinct dimensions of illness insight, i.e. treatment adherence (OSSTI-A) and identification of disease-related symptoms (OSSTI-I). CT and CG were computed using the Computational Anatomy Toolbox (CAT12). Whole-brain and regions-of-interest (ROI)-based analyses were performed. SZ patients showed higher CG in anterior cingulate, superior frontal and temporal gyrus and reduced CG in insular and superior frontal cortex when compared to HC. SZ patients showed decreased CT in pre- and paracentral, occipital, cingulate, frontoparietal and temporal regions. Illness insight in SZ patients was significantly associated with both CG and CT in the left inferior parietal lobule (OSSTI-A) and the right precentral gyrus (CG/OSSTI-A, CT/OSSTI-I). The data support a multi-parametric neuronal model with both pre- and postnatal brain developmental factors having an impact on illness insight in patients with SZ.

Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use.

Heavy cannabis use (HCU) is frequently associated with a plethora of cognitive, psychopathological and sensorimotor phenomena. Although HCU is frequent, specific patterns of abnormal brain structure and function underlying HCU in individuals presenting without cannabis-use disorder or other current and life-time major mental disorders are unclear at present. This multimodal magnetic resonance imaging (MRI) study examined resting-state functional MRI (rs-fMRI) and structural MRI (sMRI) data from 24 persons with HCU and 16 controls. Parallel independent component analysis (p-ICA) was used to examine covarying components among grey matter volume (GMV) maps computed from sMRI and intrinsic neural activity (INA), as derived from amplitude of low-frequency fluctuations (ALFF) maps computed from rs-fMRI data. Further, we used JuSpace toolbox for cross-modal correlations between MRI-based modalities with nuclear imaging derived estimates, to examine specific neurotransmitter system changes underlying HCU. We identified two transmodal components, which significantly differed between the HCU and controls (GMV: p = 0.01, ALFF p = 0.03, respectively). The GMV component comprised predominantly cerebello-temporo-thalamic regions, whereas the INA component included fronto-parietal regions. Across HCU, loading parameters of both components were significantly associated with distinct HCU behavior. Finally, significant associations between GMV and the serotonergic system as well as between INA and the serotonergic, dopaminergic and µ-opioid receptor system were detected. This study provides novel multimodal neuromechanistic insights into HCU suggesting co-altered structure/function-interactions in neural systems subserving cognitive and sensorimotor functions.

Structural correlates of sensorimotor dysfunction in heavy cannabis users.

Sensorimotor dysfunction has been previously reported in persons with cannabis dependence. Such individuals can exhibit increased levels of neurological soft signs (NSS), particularly involving motor coordination and sensorimotor integration. Whether such abnormalities may also apply to non-dependent individuals with heavy cannabis use (HCU) is unknown, as much as the neural correlates underlying such deficits. In this study, we investigated associations between NSS and gray matter volume (GMV) in males with HCU and male controls. Twenty-four persons with HCU and 17 controls were examined using standardized assessment of NSS and structural magnetic resonance imaging (MRI) at 3 T. GMV was calculated using voxel-based morphometry algorithms provided by the Computational Anatomy Toolbox (CAT12). Individuals with HCU showed higher NSS total scores compared to controls. In particular, significant NSS-subdomain effects were found for "motor coordination" (MoCo), "complex motor tasks" (CoMT), and "hard signs" (HS) expression in HCU (p < 0.05, Bonferroni-corrected). Compared to controls, persons with HCU showed significant NSS/GMV interactions in putamen and inferior frontal cortex (MoCo), right cerebellum (CoMT) and middle and superior frontal cortices, and bilateral precentral cortex and thalamus (HS). In between-group analyses, individuals with HCU showed lower GMV in the right anterior orbital and precentral gyrus, as well as higher GMV in the right superior frontal gyrus and left supplementary motor cortex compared to controls. The data support the notion of abnormal sensorimotor performance associated with HCU. The data also provide a neuromechanistic understanding of such deficits, particularly with respect to aberrant cortical-thalamic-cerebellar-cortical circuit.

Cognition and Cortical Thickness in Heavy Cannabis Users.

INTRODUCTION: Acute and long-term adverse effects of heavy cannabis use (HCU) on neurocognitive function have been suggested, as much as regional changes of brain volume. However, little is known about the relationship between impaired cognition and brain structure in individuals with HCU. OBJECTIVE: Here, we investigated associations between cognition and cortical thickness (CT) in males with HCU and male controls. METHODS: Twenty-six individuals with HCU and 20 controls were examined using a comprehensive neuropsychological test battery and high-resolution structural MRI at 3T. CT was calculated using the Computational Anatomy Toolbox (CAT12). RESULTS: Individuals with HCU differed from controls with respect to verbal learning performance and verbal working memory only. Individuals with HCU showed reduced CT in medial temporal, orbitofrontal, and cingulate regions, as well as in areas of the middle temporal and fusiform cortex (peak voxel family-wise error-corrected p < 0.001, followed by empirically determined correction for spatial extent) compared to HC. Verbal learning performance was associated with right entorhinal and left orbitofrontal CT reductions. Entorhinal CT was also significantly associated with amount and frequency of current weekly cannabis use. CONCLUSIONS: The data support the notion of domain-specific cognitive impairment in individuals with HCU and provide a neuromechanistic understanding of such deficits, particularly with respect to abnormal CT in brain areas associated with long-term memory processing.

[Cognitive control in the research domain criteria system: clinical implications for auditory verbal hallucinations]. / Kognitive Kontrolle im Research-Domain-Criteria-System: klinische Implikationen für verbale akustische Halluzinationen.

Cognitive control (CC) represents one of six constructs within the research domain criteria (RDoC) domain of cognitive systems, which can be examined using different units of analyses (from genetic and molecular mechanisms to neural circuits and self-reports). The CC is defined as the ability to execute top-down control over task-specific processes and to coordinate thought and actions to achieve a specific goal. Within the field of cognitive neuroscience, recent studies provided important findings about central neuronal components of the CC network and the interactions with other relevant functional systems. In the development and maintenance of distinct psychiatrically relevant symptoms, such as auditory verbal hallucinations (AVH) or hearing voices, dysfunctional CC is thought to play an essential transdiagnostic role. This selective literature review addresses the specific and clinically relevant question of the extent to which the RDoC construct of CC has been incorporated into studies investigating the neurobiological mechanisms of AVH. In addition, an overview of the extent to which findings exploring the underlying mechanisms have been transferred into daily clinical routine is provided. Furthermore, future research perspectives and therapeutic approaches are discussed. Based on currently preferred neurobiological models of AVH, nonpharmacological strategies, such as brain stimulation techniques and psychotherapy can be derived. Further research perspectives arise in the field of interventional studies oriented towards the RDoC matrix.

Functional Decoupling of Language and Self-Reference Networks in Patients with Persistent Auditory Verbal Hallucinations.

BACKGROUND: Accumulating neuroimaging evidence suggests that abnormal intrinsic neural activity could underlie auditory verbal hallucinations (AVH) in patients with schizophrenia. However, little is known about the functional interplay between distinct intrinsic neural networks and their association with AVH. METHODS: We investigated functional network connectivity (FNC) of distinct resting-state networks as well as the relationship between FNC strength and AVH symptom severity. Resting-state functional MRI data at 3 T were obtained for 14 healthy controls and 10 patients with schizophrenia presenting with persistent AVH. The data were analyzed using a spatial group independent component analysis, followed by constrained maximal lag correlations to determine FNC within and between groups. RESULTS: Four components of interest, comprising language, attention, executive control networks, as well as the default-mode network (DMN), were selected for subsequent FNC analyses. Patients with persistent AVH showed lower FNC between the language network and the DMN (p < 0.05, corrected for false discovery rate). FNC strength, however, was not significantly related to symptom severity, as measured by the Psychotic Symptom Rating Scale. CONCLUSION: These findings suggest that disrupted FNC between a speech-related system and a network subserving self-referential processing is associated with AVH. The data are consistent with a model of disrupted self-attribution of speech generation and perception.

Intrinsic Network Connectivity Patterns Underlying Specific Dimensions of Impulsiveness in Healthy Young Adults.

Impulsiveness is a central human personality trait and of high relevance for the development of several mental disorders. Impulsiveness is a multidimensional construct, yet little is known about dimension-specific neural correlates. Here, we address the question whether motor, attentional and non-planning components, as measured by the Barratt Impulsiveness Scale (BIS-11), are associated with distinct or overlapping neural network activity. In this study, we investigated brain activity at rest and its relationship to distinct dimensions of impulsiveness in 30 healthy young adults (m/f = 13/17; age mean/SD = 26.4/2.6 years) using resting-state functional magnetic resonance imaging at 3T. A spatial independent component analysis and a multivariate model selection strategy were used to identify systems loading on distinct impulsivity domains. We first identified eight networks for which we had a-priori hypotheses. These networks included basal ganglia, cortical motor, cingulate and lateral prefrontal systems. From the eight networks, three were associated with impulsiveness measures (p < 0.05, FDR corrected). There were significant relationships between right frontoparietal network function and all three BIS domains. Striatal and midcingulate network activity was associated with motor impulsiveness only. Within the networks regionally confined effects of age and gender were found. These data suggest distinct and overlapping patterns of neural activity underlying specific dimensions of impulsiveness. Motor impulsiveness appears to be specifically related to striatal and midcingulate network activity, in contrast to a domain-unspecific right frontoparietal system. Effects of age and gender have to be considered in young healthy samples.

Cerebellar Contributions to Persistent Auditory Verbal Hallucinations in Patients with Schizophrenia.

There is growing evidence that the cerebellum plays a crucial role in the pathophysiology of schizophrenia symptoms. Despite increasing evidence for cerebellar involvement in affective, attentive, and cognitive functions including language processing and perception, investigations of cerebellar contributions to auditory verbal hallucinations (AVH) in schizophrenia are lacking. Using structural magnetic resonance imaging at 3T, we investigated the data of 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH (pAVH), whereas the remaining ten patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Employing cerebellum-optimized segmentation techniques, i.e., the Spatially Unbiased Infratentorial Template (SUIT) toolbox, we investigated cerebellar gray matter volume (GMV) differences among the pAVH, nAVH, and a healthy control group, the magnitude of their expression between these groups and the relationship between GMV and schizophrenia symptom load. Lower GMV in pAVH patients compared to controls was found in lobules VIIb and VIIIa. Additionally, lower GMV in pAVH compared to nAVH patients was found in lobule VIIIa. A negative relationship between VIIIa GMV and overall positive symptoms was detected. Correlations with AVH-specific psychometric scores were not significant. This study shows that there are structural changes in the cognitive regions of the cerebellum that are linked to a clinical phenotype presenting with persistent positive symptoms such as AVH. The results suggest that the cerebellum and its associated neural circuits do play a role in the emergence of positive symptoms in schizophrenia, but probably not exclusively in AVH symptom expression.

Baseline brain perfusion and brain structure in patients with major depression: a multimodal magnetic resonance imaging study.

BACKGROUND: Abnormal regional cerebral blood flow (rCBF) and grey matter volume have been frequently reported in patients with major depressive disorder (MDD). However, it is unclear to what extent structural and functional change co-occurs in patients with MDD and whether markers of neural activity, such as rCBF, can be predicted by structural change. METHODS: Using MRI, we investigated resting-state rCBF and brain structure in patients with MDD and healthy controls between July 2008 and January 2013. We acquired perfusion images obtained with continuous arterial spin labelling, used voxel-based morphometry to assess grey matter volume and integrated biological parametric mapping analyses to investigate the impact of brain atrophy on rCBF. RESULTS: We included 43 patients and 29 controls in our study. Frontotemporal grey matter volume was reduced in patients compared with controls. In patients, rCBF was reduced in the anterior cingulate and bilateral parahippocampal areas and increased in frontoparietal and striatal regions. These abnormalities were confirmed by analyses with brain volume as a covariate. In patients with MDD there were significant negative correlations between the extent of depressive symptoms and bilateral parahippocampal rCBF. We found a positive correlation between depressive symptoms and rCBF for right middle frontal cortical blood flow. LIMITATIONS: Medication use in patients has to be considered as a limitation of our study. CONCLUSION: Our data suggest that while changes of cerebral blood flow and brain volume co-occur in patients with MDD, structural change is not sufficient to explain altered neural activity in patients at rest. Abnormal brain structure and function in patients with MDD appear to reflect distinct levels of neuropathology.

Cigarette smoking modulates medication-associated deficits in a monetary reward task in patients with schizophrenia.

Imaging studies of reward processing have demonstrated a mesolimbic-mesocortical dopaminergic dysfunction in schizophrenia. Such studies on reward processing in patients and also in healthy controls showed that differential activations of dopaminergic brain areas are associated with adaptive changes in response speed related to different reward values. Given this relationship, we investigated reward processing on the behavioural level in a larger sample of 49 medicated patients with a diagnosis of schizophrenia (ICD-10 F20) and 49 healthy controls. Subjects were instructed to react by button press upon two different stimuli in order to retain a 60 % chance winning a previously announced high (1$) or low (20¢) amount of money paid to participants after the experiment. Concordant with previous reports on deficits in reward processing, acceleration of reaction times in patients upon low rewards differed significantly (p < 0.05) from healthy controls in our present behavioural study. This effect was pronounced in the non-smoking subgroup of patients (n = 24). In this subgroup, we also observed a significant (p < 0.05) positive correlation with medication type (relatively high vs. low D2 receptor affinity) and with the PANSS score, the latter with a trend to significance (p = 0.08). Our study demonstrates that reaction time measures in a monetary reward task might constitute a feasible behavioural proxy for dopaminergic dysfunction and its different dimensions regarding psychopathology but also medication in patients with schizophrenia. In line with clinical observations, our findings support the notion that smoking modulates medication-associated side effects on reward processing in patients with schizophrenia.

Cognitive domain-independent aberrant frontoparietal network strength in individuals with excessive smartphone use.

Excessive smartphone use (ESU) may fulfill criteria for addictive behavior. In contrast to other related behavioral addictions, particularly Internet Gaming Disorder, little is known about the neural correlates underlying ESU. In this study, we used functional magnetic resonance imaging (fMRI) to acquire task data from three distinct behavioral paradigms, i.e. cue-reactivity, inhibition, and working memory, in individuals with psychometrically defined ESU (n = 19) compared to controls (n-ESU; n = 20). The Smartphone Addiction Inventory (SPAI) was used to quantify ESU-severity according to a novel five-factor model (SPAI-I). A multivariate data fusion approach, i.e. joint Independent Component Analysis (jICA) was employed to analyze fMRI-data derived from three separate experimental conditions, but analyzed jointly to detect converging and domain-independent neural signatures that differ between persons with vs. those without ESU. Across the three functional tasks, jICA identified a predominantly frontoparietal system that showed lower network strength in individuals with ESU compared to n-ESU (p < 0.05 FDR-corrected). Furthermore, significant associations between frontoparietal network strength and SPAI-I's dimensions "time spent" and "craving" were found. The data suggest a frontoparietal cognitive control network as cognitive domain-independent neural signature of excessive and potentially addictive smartphone use.

Aberrant intrinsic neural network strength in individuals with "smartphone addiction": An MRI data fusion study.

BACKGROUND AND OBJECTIVES: Excessive smartphone use, also referred to as "smartphone addiction" (SPA), has increasingly attracted neuroscientific interest due to its similarities with other behavioral addictions, particularly internet gaming disorder. Little is known about the neural mechanisms underlying smartphone addiction. We explored interrelationships between brain structure and function to specify neurobiological correlates of SPA on a neural system level. METHODS: Gray matter volume (GMV) and intrinsic neural activity (INA) were investigated in individuals with SPA (n = 20) and controls (n = 24), using multimodal magnetic resonance imaging and multivariate data fusion techniques, that is, parallel independent component analysis. RESULTS: The joint analysis of both data modalities explored shared information between GMV and INA. In particular, two amplitudes of low frequency fluctuations-based independent neural systems significantly differed between individuals with SPA and controls. A medial/dorsolateral prefrontal system exhibited lower functional network strength in individuals with SPA versus controls, whereas the opposite pattern was detected in a parietal cortical/cerebellar system. Neural network strength was significantly related to duration of smartphone use and sleep difficulties. DISCUSSION AND CONCLUSIONS: We show modality-specific associations of the brain's resting-state activity with distinct and shared SPA symptom dimensions. In particular, the data suggest contributions of aberrant prefrontal and parietal neural network strength as a possible signature of deficient executive control in SPA. SCIENTIFIC SIGNIFICANCE: This study suggests distinct neural mechanisms underlying specific biological and behavioral dimensions of excessive smartphone use.

Cortical surface variation in individuals with excessive smartphone use.

Excessive smartphone use has been repeatedly related to adverse effects on mental health and psychological well-being in young adults. The continued investigation of the neurobiological mechanism underlying excessive smartphone use-sometimes also referred to as "smartphone addiction"(SPA)-is considered a top priority in system neuroscience research. Despite progress in the past years, cortical morphology associated with SPA is still poorly understood. Here, we used structural magnetic resonance imaging (MRI) at 3 T to investigate two cortical surface markers of distinct neurodevelopmental origin such as the complexity of cortical folding (CCF) and cortical thickness (CTh) in individuals with excessive smartphone use (n = 19) compared to individuals not fulfilling SPA criteria (n-SPA; n = 22). SPA was assessed using the Smartphone Addiction Inventory (SPAI). CCF and CTh were investigated using the Computational Anatomy Toolbox (CAT12). SPA individuals showed lower CCF in the right superior frontal gyrus as well as in the right caudal (cACC) and rostral anterior cingulate cortex (rACC) compared to n-SPA individuals (TFCE, uncorrected at p < 0.001). Following a dimensional approach, across the entire sample, CCF of the right cACC was significantly associated with SPAI total score, as well as with distinct SPAI subdimensions, particularly time spent with the device, compulsivity, and sleep interference in all participants (n = 41; p < 0.05, FDR-corrected). Collectively, these findings suggest that SPA is associated with aberrant structural maturation of regions important for cognitive control and emotional regulation.

Neural correlates of cue reactivity in individuals with smartphone addiction.

Popularity of smartphones has dramatically increased in the past years, accompanied by increased concerns regarding potentially adverse effects on physical and mental health. Addictive behavior associated with excessive smartphone use, frequently referred to as "smartphone addiction" (SPA), has attracted increased scientific interest. However the neural correlates of SPA are unknown. We used functional magnetic resonance imaging at 3T to investigate the neural correlates of cue reactivity (CR) in individuals with SPA (n = 21) compared to controls (n = 21). SPA was assessed using the Smartphone Addiction Inventory (SPAI), and neural activity was measured by a modified CR task. Contrasts of images of smartphones vs. neutral stimuli and stimuli including active vs. inactive smartphones (p < 0.001, uncorrected for height, followed by correction for spatial extent) were analyzed. In the first contrast, group differences in medial prefrontal (MPFC), occipital, temporal, and anterior cingulate (ACC) cortices, in temporoparietal regions, and cerebellum were found. For active vs. inactive smartphones, group differences were found in frontal operculum/anterior insula and precentral gyrus. Negative correlations were found between MPFC, ACC, precuneus, and precentral gyrus and specific SPAI subscores, i.e. compulsive behavior, functional impairment and withdrawal. This study suggests spatial similarities of CR-related brain activation between addictive smartphone use and other well-known addictive disorders.