Distinct Volume Alterations of Thalamic Nuclei Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. STUDY DESIGN: We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. STUDY RESULTS: We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. CONCLUSIONS: Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia.

Basal-Forebrain Cholinergic Nuclei Alterations are Associated With Medication and Cognitive Deficits Across the Schizophrenia Spectrum.

BACKGROUND AND HYPOTHESIS: The cholinergic system is altered in schizophrenia. Particularly, patients' volumes of basal-forebrain cholinergic nuclei (BFCN) are lower and correlated with attentional deficits. It is unclear, however, if and how BFCN changes and their link to cognitive symptoms extend across the schizophrenia spectrum, including individuals with at-risk mental state for psychosis (ARMS) or during first psychotic episode (FEP). STUDY DESIGN: To address this question, we assessed voxel-based morphometry (VBM) of structural magnetic resonance imaging data of anterior and posterior BFCN subclusters as well as symptom ratings, including cognitive, positive, and negative symptoms, in a large multi-site dataset (n = 4) comprising 68 ARMS subjects, 98 FEP patients (27 unmedicated and 71 medicated), 140 patients with established schizophrenia (SCZ; medicated), and 169 healthy controls. RESULTS: In SCZ, we found lower VBM measures for the anterior BFCN, which were associated with the anticholinergic burden of medication and correlated with patients' cognitive deficits. In contrast, we found larger VBM measures for the posterior BFCN in FEP, which were driven by unmedicated patients and correlated at-trend with cognitive deficits. We found no BFCN changes in ARMS. Altered VBM measures were not correlated with positive or negative symptoms. CONCLUSIONS: Results demonstrate complex (posterior vs. anterior BFCN) and non-linear (larger vs. lower VBM) differences in BFCN across the schizophrenia spectrum, which are specifically associated both with medication, including its anticholinergic burden, and cognitive symptoms. Data suggest an altered trajectory of BFCN integrity in schizophrenia, influenced by medication and relevant for cognitive symptoms.

Negative symptoms, striatal dopamine and model-free reward decision-making in schizophrenia.

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making ('reward prediction influence', RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms.

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review.

For decades, aberrant dopamine transmission has been proposed to play a central role in schizophrenia pathophysiology. These theories are supported by human in vivo molecular imaging studies of dopamine transmission, particularly positron emission tomography. However, there are several downsides to such approaches, for example limited spatial resolution or restriction of the measurement to synaptic processes of dopaminergic neurons. To overcome these limitations and to measure complementary aspects of dopamine transmission, magnetic resonance imaging (MRI)-based approaches investigating the macrostructure, metabolism, and connectivity of dopaminergic nuclei, i.e., substantia nigra pars compacta and ventral tegmental area, can be employed. In this scoping review, we focus on four dopamine MRI methods that have been employed in patients with schizophrenia so far: neuromelanin MRI, which is thought to measure long-term dopamine function in dopaminergic nuclei; morphometric MRI, which is assumed to measure the volume of dopaminergic nuclei; diffusion MRI, which is assumed to measure fiber-based structural connectivity of dopaminergic nuclei; and resting-state blood-oxygenation-level-dependent functional MRI, which is thought to measure functional connectivity of dopaminergic nuclei based on correlated blood oxygenation fluctuations. For each method, we describe the underlying signal, outcome measures, and downsides. We present the current state of research in schizophrenia and compare it to other disorders with either similar (psychotic) symptoms, i.e., bipolar disorder and major depressive disorder, or dopaminergic abnormalities, i.e., substance use disorder and Parkinson's disease. Finally, we discuss overarching issues and outline future research questions.

Frequency-specific coactivation patterns in resting-state and their alterations in schizophrenia: An fMRI study.

The resting-state human brain is a dynamic system that shows frequency-dependent characteristics. Recent studies demonstrate that coactivation pattern (CAP) analysis can identify recurring brain states with similar coactivation configurations. However, it is unclear whether and how CAPs depend on the frequency bands. The current study investigated the spatial and temporal characteristics of CAPs in the four frequency sub-bands from slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), slow-3 (0.073-0.198 Hz), to slow-2 (0.198-0.25 Hz), in addition to the typical low-frequency range (0.01-0.08 Hz). In the healthy subjects, six CAP states were obtained at each frequency band in line with our prior study. Similar spatial patterns with the typical range were observed in slow-5, 4, and 3, but not in slow-2. While the frequency increased, all CAP states displayed shorter persistence, which caused more between-state transitions. Specifically, from slow-5 to slow-4, the coactivation not only changed significantly in distributed cortical networks, but also increased in the basal ganglia as well as the amygdala. Schizophrenia patients showed significant alteration in the persistence of CAPs of slow-5. Using leave-one-pair-out, hold-out and resampling validations, the highest classification accuracy (84%) was achieved by slow-4 among different frequency bands. In conclusion, our findings provide novel information about spatial and temporal characteristics of CAP states at different frequency bands, which contributes to a better understanding of the frequency aspect of biomarkers for schizophrenia and other disorders.

Common and specific large-scale brain changes in major depressive disorder, anxiety disorders, and chronic pain: a transdiagnostic multimodal meta-analysis of structural and functional MRI studies.

Major depressive disorder (MDD), anxiety disorders (ANX), and chronic pain (CP) are closely-related disorders with both high degrees of comorbidity among them and shared risk factors. Considering this multi-level overlap, but also the distinct phenotypes of the disorders, we hypothesized both common and disorder-specific changes of large-scale brain systems, which mediate neural mechanisms and impaired behavioral traits, in MDD, ANX, and CP. To identify such common and disorder-specific brain changes, we conducted a transdiagnostic, multimodal meta-analysis of structural and functional MRI-studies investigating changes of gray matter volume (GMV) and intrinsic functional connectivity (iFC) of large-scale intrinsic brain networks across MDD, ANX, and CP. The study was preregistered at PROSPERO (CRD42019119709). 320 studies comprising 10,931 patients and 11,135 healthy controls were included. Across disorders, common changes focused on GMV-decrease in insular and medial-prefrontal cortices, located mainly within the so-called default-mode and salience networks. Disorder-specific changes comprised hyperconnectivity between default-mode and frontoparietal networks and hypoconnectivity between limbic and salience networks in MDD; limbic network hyperconnectivity and GMV-decrease in insular and medial-temporal cortices in ANX; and hypoconnectivity between salience and default-mode networks and GMV-increase in medial temporal lobes in CP. Common changes suggested a neural correlate for comorbidity and possibly shared neuro-behavioral chronification mechanisms. Disorder-specific changes might underlie distinct phenotypes and possibly additional disorder-specific mechanisms.

Human threat circuits: Threats of pain, aggressive conspecific, and predator elicit distinct BOLD activations in the amygdala and hypothalamus.

Introduction: Threat processing, enabled by threat circuits, is supported by a remarkably conserved neural architecture across mammals. Threatening stimuli relevant for most species include the threat of being attacked by a predator or an aggressive conspecific and the threat of pain. Extensive studies in rodents have associated the threats of pain, predator attack and aggressive conspecific attack with distinct neural circuits in subregions of the amygdala, the hypothalamus and the periaqueductal gray. Bearing in mind the considerable conservation of both the anatomy of these regions and defensive behaviors across mammalian species, we hypothesized that distinct brain activity corresponding to the threats of pain, predator attack and aggressive conspecific attack would also exist in human subcortical brain regions. Methods: Forty healthy female subjects underwent fMRI scanning during aversive classical conditioning. In close analogy to rodent studies, threat stimuli consisted of painful electric shocks, a short video clip of an attacking bear and a short video clip of an attacking man. Threat processing was conceptualized as the expectation of the aversive stimulus during the presentation of the conditioned stimulus. Results: Our results demonstrate differential brain activations in the left and right amygdala as well as in the left hypothalamus for the threats of pain, predator attack and aggressive conspecific attack, for the first time showing distinct threat-related brain activity within the human subcortical brain. Specifically, the threat of pain showed an increase of activity in the left and right amygdala and the left hypothalamus compared to the threat of conspecific attack (pain > conspecific), and increased activity in the left amygdala compared to the threat of predator attack (pain > predator). Threat of conspecific attack revealed heightened activity in the right amygdala, both in comparison to threat of pain (conspecific > pain) and threat of predator attack (conspecific > predator). Finally, for the condition threat of predator attack we found increased activity in the bilateral amygdala and the hypothalamus when compared to threat of conspecific attack (predator > conspecific). No significant clusters were found for the contrast predator attack > pain. Conclusion: Results suggest that threat type-specific circuits identified in rodents might be conserved in the human brain.

Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia.

A potential pathophysiological mechanism of cognitive difficulties in schizophrenia is a dysregulated cholinergic system. Particularly, the cholinergic basal forebrain nuclei (BFCN), the source of cortical cholinergic innervation, support multiple cognitive functions, ranging from attention to decision-making. We hypothesized that BFCN structural integrity is altered in schizophrenia and associated with patients' attentional deficits. We assessed gray matter (GM) integrity of cytoarchitectonically defined BFCN region-of-interest in 72 patients with schizophrenia and 73 healthy controls, matched for age and gender, from the COBRE open-source database, via structural magnetic resonance imaging (MRI)-based volumetry. MRI-derived measures of GM integrity (i.e., volumes) were linked with performance on a symbol coding task (SCT), a paper-pencil-based metric that assesses attention, by correlation and mediation analysis. To assess the replicability of findings, we repeated the analyses in an independent dataset comprising 26 patients with schizophrenia and 24 matched healthy controls. BFCN volumes were lower in patients (t(139)=2.51, p = 0.01) and significantly associated with impaired SCT performance (r = 0.31, p = 0.01). Furthermore, lower BFCN volumes mediated the group difference in SCT performance. When including global GM volumes, which were lower in patients, as covariates-of-no-interest, these findings disappeared, indicating that schizophrenia did not have a specific effect on BFCN relative to other regional volume changes. We replicated these findings in the independent cohort, e.g., BFCN volumes were lower in patients and mediated patients' impaired SCT performance. Results demonstrate lower BFCN volumes in schizophrenia, which link with patients' attentional deficits. Data suggest that a dysregulated cholinergic system might contribute to cognitive difficulties in schizophrenia via impaired BFCN.

Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum.

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.

Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia.

Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine's topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia.

Your presence soothes me: a neural process model of aversive emotion regulation via social buffering.

The reduction of aversive emotions by a conspecific's presence-called social buffering-is a universal phenomenon in the mammalian world and a powerful form of human social emotion regulation. Animal and human studies on neural pathways underlying social buffering typically examined physiological reactions or regional brain activations. However, direct links between emotional and social stimuli, distinct neural processes and behavioural outcomes are still missing. Using data of 27 female participants, the current study delineated a large-scale process model of social buffering's neural underpinnings, connecting changes in neural activity to emotional behaviour by means of voxel-wise multilevel mediation analysis. Our results confirmed that three processes underlie human social buffering: (i) social support-related reduction of activity in the orbitofrontal cortex, ventromedial and dorsolateral prefrontal cortices, anterior and mid-cingulate; (ii) downregulation of aversive emotion-induced brain activity in the superficial cortex-like amygdala and mediodorsal thalamus; and (iii) downregulation of reported aversive feelings. Results of the current study provide evidence for a distinct neural process model of aversive emotion regulation in humans by social buffering.

Impact of non-uniform attenuation correction in a dynamic [18F]-FDOPA brain PET/MRI study.

BACKGROUND: PET (positron emission tomography) biokinetic modelling relies on accurate quantitative data. One of the main corrections required in PET imaging to obtain high quantitative accuracy is tissue attenuation correction (AC). Incorrect non-uniform PET-AC may result in local bias in the emission images, and thus in relative activity distributions and time activity curves for different regions. MRI (magnetic resonance imaging)-based AC is an active area of research in PET/MRI neuroimaging, where several groups developed in the last few years different methods to calculate accurate attenuation (µ-)maps. Some AC methods have been evaluated for different PET radioisotopes and pathologies. However, AC in PET/MRI has scantly been investigated in dynamic PET studies where the aim is to get quantitative kinetic parameters, rather than semi-quantitative parameters from static PET studies. In this work, we investigated the impact of AC accuracy in PET image absolute quantification and, more importantly, in the slope of the Patlak analysis based on the simplified reference tissue model, from a dynamic [18F]-fluorodopa (FDOPA) PET/MRI study. In the study, we considered the two AC methods provided by the vendor and an in-house AC method based on the dual ultrashort time echo MRI sequence, using as reference a multi-atlas-based AC method based on a T1-weighted MRI sequence. RESULTS: Non-uniform bias in absolute PET quantification across the brain, from - 20% near the skull to - 10% in the central region, was observed using the two vendor's µ-maps. The AC method developed in-house showed a - 5% and 1% bias, respectively. Our study resulted in a 5-9% overestimation of the PET kinetic parameters with the vendor-provided µ-maps, while our in-house-developed AC method showed < 2% overestimation compared to the atlas-based AC method, using the cerebellar cortex as reference region. The overestimation obtained using the occipital pole as reference region resulted in a 7-10% with the vendor-provided µ-maps, while our in-house-developed AC method showed < 6% overestimation. CONCLUSIONS: PET kinetic analyses based on a reference region are especially sensitive to the non-uniform bias in PET quantification from AC inaccuracies in brain PET/MRI. Depending on the position of the reference region and the bias with respect to the analysed region, kinetic analyses suffer different levels of bias. Considering bone in the µ-map can potentially result in larger errors, compared to the absence of bone, when non-uniformities in PET quantification are introduced.

Cognitive reward control recruits medial and lateral frontal cortices, which are also involved in cognitive emotion regulation: A coordinate-based meta-analysis of fMRI studies.

Cognitive reward control (CRC) refers to the cognitive control of one's craving for hedonic stimuli, like food, sex, or drugs. Numerous functional magnetic resonance imaging (fMRI) studies have investigated neural sources of CRC. However, a consistent pattern of brain activation across stimulus types has not been identified so far. We addressed this question using coordinate-based meta-analysis of task-fMRI studies during CRC. To further characterize such a potential common CRC activation pattern, we extended our approach to three additional questions: (i) Do CRC meta-analytic results overlap with those during the control of emotional states, such as in cognitive regulation of aversive emotions (cognitive emotion regulation, CER)? (ii) How does the control of motivational/emotional states link to the control of action states with less motivational/emotional valence such as in response inhibition paradigms, i.e., do meta-anyltic result maps overlap? (iii) Does the control of motivational/emotional states constitute a consistent pattern of organized (i.e., coherent) ongoing or intrinsic brain activity? This question was tested by a seed-based intrinsic functional connectivity (iFC) analysis in an independent data set of resting-state fMRI. We found consistent CRC activation mainly in supplementary motor, dorsolateral prefrontal, and ventrolateral prefrontal cortices across studies. This activation pattern overlapped largely with CER-related activation, except for left-sided lateral temporal and parietal cortex activation, which was more pronounced during CER. It overlapped partly with activation during response inhibition in (pre-)supplementary motor, insular, and parietal cortices, but differed from it in dorsolateral and ventrolateral prefrontal cortices. Furthermore, it remarkably defined an iFC network covering activation patterns of both CRC and CER. Results demonstrate a consistent activation pattern of CRC across stimulus types, which overlaps largely with those of CER but only partly with those of response inhibition and constitutes an intrinsic co-activity network. These data suggest a common mechanism for the cognitive control of both motivational and emotional stimuli.

Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms.

While there is consistent evidence for increased presynaptic dopamine synthesis capacity in the striatum of patients with schizophrenia during psychosis, it is unclear whether this also holds for patients during psychotic remission. This study investigates whether striatal dopamine synthesis capacity is altered in patients with schizophrenia during symptomatic remission of positive symptoms, and whether potential alterations relate to symptoms other than positive, such as cognitive difficulties. Twenty-three patients with schizophrenia in symptomatic remission of positive symptoms according to Andreasen, and 24 healthy controls underwent 18F-DOPA-PET and behavioural-cognitive assessment. Imaging data were analysed with voxel-wise Patlak modelling with cerebellum as reference region, resulting in the influx constant kicer reflecting dopamine synthesis capacity. For the whole striatum and its subdivisions (i.e. limbic, associative, and sensorimotor), averaged regional kicer values were calculated, compared across groups, and correlated with behavioural-cognitive scores, including a mediation analysis. Patients had negative symptoms (Positive and Negative Syndrome Scale-negative 14.13 ± 5.91) and cognitive difficulties, i.e. they performed worse than controls in Trail-Making-Test-B (TMT-B; P = 0.01). Furthermore, kicer was reduced in patients for whole striatum (P = 0.004) and associative (P = 0.002) and sensorimotor subdivisions (P = 0.007). In patients, whole striatum kicer was negatively correlated with TMT-B (rho = -0.42, P = 0.04; i.e. the lower striatal kicer, the worse the cognitive performance). Mediation analysis showed that striatal kicer mediated the group difference in TMT-B. Results demonstrate that patients with schizophrenia in symptomatic remission of positive symptoms have decreased striatal dopamine synthesis capacity, which mediates the disorder's impact on cognitive difficulties. Data suggest that striatal dopamine dysfunction contributes to cognitive difficulties in schizophrenia.

Specific Substantial Dysconnectivity in Schizophrenia: A Transdiagnostic Multimodal Meta-analysis of Resting-State Functional and Structural Magnetic Resonance Imaging Studies.

BACKGROUND: This study investigated characteristic large-scale brain changes in schizophrenia. Numerous imaging studies have demonstrated brain changes in schizophrenia, particularly aberrant intrinsic functional connectivity (iFC) of ongoing brain activity, measured by resting-state functional magnetic resonance imaging, and aberrant gray matter volume (GMV) of distributed brain regions, measured by structural magnetic resonance imaging. It is unclear, however, which iFC changes are specific to schizophrenia compared with those of other disorders and whether such specific iFC changes converge with GMV changes. To address this question of specific substantial dysconnectivity in schizophrenia, we performed a transdiagnostic multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies in schizophrenia and other psychiatric disorders. METHODS: Multiple databases were searched up to June 2017 for whole-brain seed-based iFC studies and voxel-based morphometry studies in schizophrenia, major depressive disorder, bipolar disorder, addiction, and anxiety. Coordinate-based meta-analyses were performed to detect 1) schizophrenia-specific hyperconnectivity or hypoconnectivity of intrinsic brain networks (compared with hyperconnectivity or hypoconnectivity of each other disorder both separately and combined across comparisons) and 2) the overlap between dysconnectivity and GMV changes (via multimodal conjunction analysis). RESULTS: For iFC meta-analysis, 173 publications comprising 4962 patients and 4575 control subjects were included, and for GMV meta-analysis, 127 publications comprising 6311 patients and 6745 control subjects were included. Disorder-specific iFC dysconnectivity in schizophrenia (consistent across comparisons with other disorders) was found for limbic, frontoparietal executive, default mode, and salience networks. Disorder-specific dysconnectivity and GMV reductions converged in insula, lateral postcentral cortex, striatum, and thalamus. CONCLUSIONS: Results demonstrated specific substantial dysconnectivity in schizophrenia in insula, lateral postcentral cortex, striatum, and thalamus. Data suggest that these regions are characteristic targets of schizophrenia.

The Role of Brain Connectome Imaging in the Estimation of Depressive Relapse Risk.

BACKGROUND: About two-thirds of all patients with major depressive disorder (MDD) suffer from depressive relapse, the mechanisms of which are still poorly understood. In recent years, analyses of the brain's connectome have increasingly been employed to identify potential biomarkers of depressive relapse. The term "connectome" refers to the map of all structural or functional connections in the brain. It can be investigated by structural or functional magnetic resonance imaging followed by graph theory-based analysis to characterize network topology on the global and regional level. METHODS: This review is based on a selective literature search in PubMed representing the current state of research, as well as on an already published study which was awarded the Promotionspreis of the Deutsche Röntgengesellschaft. RESULTS AND CONCLUSION: Numerous studies point to altered network topology, e. g., of default-mode network and striatum, as being crucial for the pathophysiology of MDD. Our group was able to show that striatal centrality (or hubness) is associated with the number of depressive episodes, which is one of the best predictors for depressive relapse. These data suggest aberrant striatal network topology as a potential biomarker for depressive relapse risk. The translation of these promising findings into clinical routine diagnostics is promoted by several methodological advantages, while some unresolved issues still hinder this process. KEY POINTS: · About two-thirds of all patients with MDD suffer from depressive relapse.. · The mechanisms of depressive relapse are still poorly understood.. · Imaging the brain's connectome can contribute to better understanding of depressive relapse.. · The term "connectome" comprises all structural and functional connections of the brain.. · Altered striatal network topology could be associated with depressive relapse risk.. CITATION FORMAT: · Brandl F, Meng C, Zimmer C et al. The Role of Brain Connectome Imaging in the Estimation of Depressive Relapse Risk. Fortschr Röntgenstr 2018; 190: 1036 - 1043.

Cortico-thalamic hypo- and hyperconnectivity extend consistently to basal ganglia in schizophrenia.

Schizophrenia is characterized by hypoconnectivity or decreased intrinsic functional connectivity (iFC) between prefrontal-limbic cortices and thalamic nuclei, as well as hyperconnectivity or increased iFC between primary-sensorimotor cortices and thalamic nuclei. However, cortico-thalamic iFC overlaps with larger, structurally defined cortico-striato-pallido-thalamo-cortical (CSPTC) circuits. If such an overlap is relevant for intrinsic hypo-/hyperconnectivity, it suggests (i) that patterns of cortico-subcortical hypo-/hyperconnectivity extend consistently from thalamus to basal ganglia nuclei; and (ii) such consistent hypo-/hyperconnectivity might link distinctively but consonant with different symptom dimensions, namely cognitive and psychotic impairments. To test this hypothesis, 57 patients with schizophrenia and 61 healthy controls were assessed by resting-state functional magnetic resonance imaging (fMRI) and clinical-behavioral testing. IFC from intrinsic cortical networks into thalamus, striatum, and pallidum was estimated by partial correlations between fMRI time courses. In patients, the salience network covering prefrontal-limbic cortices was hypoconnected with the mediodorsal thalamus and ventral parts of striatum and pallidum; these iFC-hypoconnectivity patterns were correlated both among each other and specifically with patients' impaired cognition. In contrast, the auditory-sensorimotor network covering primary-sensorimotor cortices was hyperconnected with the anterior ventral nucleus of the thalamus and dorsal parts of striatum and pallidum; these iFC-hyperconnectivity patterns were likewise correlated among each other and specifically with patients' psychotic symptoms. The results demonstrate that prefrontal-limbic hypoconnectivity and primary-sensorimotor hyperconnectivity extend consistently across subcortical nuclei and specifically across distinct symptom dimensions. Data support the model of consistent cortico-subcortical hypo-/hyperconnectivity within CSPTC circuits in schizophrenia.

Decoupling of Local Metabolic Activity and Functional Connectivity Links to Amyloid in Alzheimer's Disease.

BACKGROUND: Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer's disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region's sensitivity to afferent input from other regions, i.e., FC. OBJECTIVE: We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-ß pathology (Aß). METHODS: Healthy adults (n=20) and Aß+patients without memory impairment (n=9), early MCI (n=21), late MCI (n=18) and AD (n=22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aß of the pDMN. Coupling between LMA and FC (rLA/FC) was estimated by voxelwise correlation. RESULTS: RLMA/FC decreased with disease severity (F=20.09, p<0.001). This decrease was specifically associated with pDMN Aß (r=-0.273, p=0.029) but not global Aß (r=-0.112, p=0.378) and with the impact of Aß on FC (i.e., rAß/FC,r=-0.339; p=0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aß, pDMN Aß, pDMN LMA, and pDMN FC, respectively. CONCLUSION: Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aß and contributes to memory decline.