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Previous studies using imaging techniques such as electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) have identified neurophysiological markers of impaired feedback processing in patients with Borderline Personality Disorder (BPD). These mainly include reduced oscillatory activity in the theta frequency range in the EEG and altered activations in frontal and striatal regions in fMRI studies. The aim of the present study is to integrate these results using a coupling of simultaneously recorded EEG and fMRI. Simultaneous EEG (64-channel) and fMRI (3-Tesla Siemens Prisma) was recorded whilst participants (19 BPD patients and 18 controls) performed a gambling task. Data was analysed for the two imaging techniques separately as well as in a single-trial coupling of both modalities. Evoked theta oscillatory power as a response to loss feedback was reduced in BPD patients. EEG-fMRI coupling revealed an interaction between feedback valence and group in prefrontal regions centering in the dorsolateral prefrontal cortex (dlPFC), with healthy controls showing stronger modulation by theta responses during loss when compared to gain feedback and the opposite effect in BPD patients. Our results show multiple alterations in the processing of feedback in BPD, which were partly linked to impulsivity. The dlPFC was identified as the seed of theta-associated activation differences., (© 2021. The Author(s).)

Background: Reasoning biases such as the jumping-to-conclusions bias (JTC) are thought to contribute to delusions. Interventions targeting these biases such as metacognitive training (MCT) may improve delusions. So far, it is not clear whether JTC depends on dopaminergic reward areas that constitute the main action locus of antipsychotic drugs, or on additional cortical areas. The present study aimed to investigate fMRI activation and functional connectivity patterns underlying JTC, and their changes following MCT, in patients with delusions., Methods: Participants were 25 healthy individuals and 26 patients with current delusions who were either medication-free or on stable medication without sufficient response. We assessed (1) BOLD activity in the task-positive (TPN), task-negative (TNN), and subcortical reward network (RN); (2) Psychophysiological interactions (PPI) of peak activation areas., Results: Presence of JTC (irrespective of group) was associated with lower RN activity during conclusion events, and with increased effective connectivity between TPN and TNN during draw events. Following MCT, changes were observed in TPN activity and in effective connectivity of inferior parietal cortex (part of the TPN) with all three target networks., Conclusion: JTC is associated not only with reward system areas that constitute the main target of antipsychotic drugs, but also with cortical areas, particularly of the TPN.

Progress in the understanding of normal and disturbed brain function is critically dependent on the methodological approach that is applied. Both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are extremely efficient methods for the assessment of human brain function. The specific appeal of the combination is related to the fact that both methods are complementary in terms of basic aspects: EEG is a direct measurement of neural mass activity and provides high temporal resolution. FMRI is an indirect measurement of neural activity and based on hemodynamic changes, and offers high spatial resolution. Both methods are very sensitive to changes of synaptic activity, suggesting that with simultaneous EEG and fMRI the same neural events can be characterized with both high temporal and spatial resolution. Since neural oscillations that can be assessed with EEG are a key mechanism for multi-site communication in the brain, EEG-fMRI can offer new insights into the connectivity mechanisms of brain networks.

Neurobiological correlates of various treatment approaches (e.g. psychopharmacology, cognitive behavioural therapy) have become an important issue in recent neuroimaging studies. In schizophrenia, dysfunctions especially in frontal and parietal brain regions as well as the ventral striatum have been demonstrated in numerous studies. The review includes functional MRI studies about neurobiological correlates of treatment effects in schizophrenic patients. Treatment-associated changes in brain activity were shown especially in the anterior cingulate cortex, the dorsolateral prefrontal cortex, the ventral striatum and the amygdala. In addition, the differential effects of various treatment approaches including different neuroleptics (atypical neuroleptics, typical neuroleptics) as well as cognitive behavioural therapy will be considered in this review. The influence of functional differences on the differential effect of typical and atypical antipsychotics on cognitive functions will be discussed.

Over the last few years, neuroimaging techniques have contributed greatly to the identification of the structural and functional neuroanatomy of anxiety disorders. The amygdala seems to be a crucial structure for fear and anxiety, and has consistently been found to be activated in anxiety-provoking situations. Apart from the amygdala, the insula and anterior cinguiate cortex seem to be critical, and ail three have been referred to as the "fear network." In the present article, we review the main findings from three major lines of research. First, we examine human models of anxiety disorders, including fear conditioning studies and investigations of experimentally induced panic attacks. Then we turn to research in patients with anxiety disorders and take a dose look at post-traumatic stress disorder and obsessive-compulsive disorder. Finally, we review neuroimaging studies investigating neural correlates of successful treatment of anxiety, focusing on exposure-based therapy and several pharmacological treatment options, as well as combinations of both.

Single-trial coupling of simultaneously recorded EEG and fMRI time-series can be used to generate fMRI patterns of brain activity with high spatial resolution from EEG responses with high temporal resolution. A forced choice reaction task under different effort conditions has been previously used to demonstrate single-trial EEG-fMRI coupling effects for an early ERP component (N1: 70-150 ms) measured on a single scalp channel (Cz), thereby providing the first multi-modal evidence of early anterior cingulate cortex (ACC) activation in effortful decision making (Mulert, C., Seifert, C., Leicht, G., Kirsch, V., Ertl, M., Karch, S., Moosmann, M., Lutz, J., Möller, H.J., Hegerl, U., Pogarell, O., Jäger, L., 2008. Single-trial coupling of EEG and fMRI reveals the involvement of early anterior cingulate cortex activation in effortful decision making. Neuroimage 42, 158-168.). In this work, we searched for "effort-specific" ERP-N1 sources and explored their single-trial EEG-fMRI correlations for discovering "source-specific" inter-modality coupling effects. To this end, we performed a whole-cortex distributed ERP analysis and used the local source power trial-by-trial variation as an input for single-trial EEG-fMRI coupling analysis. We found a high-effort-specific ERP-N1 source in the ACC and statistically significant differential EEG-fMRI coupling spots in five cortical regions, including the ACC. Our results provide new insights about the neural origins of effort-specific EEG and fMRI response modulations in a choice reaction task and confirm the central role of early ACC activation in motivation-related decision making processes; we discuss the importance of combining distributed source modeling with single-trial coupling for enriching the interpretation of EEG-fMRI patterns.

Different EEG-vigilance stages from full alertness to sleep onset can be separated during rest. Also fMRI research recently focused on the resting condition and identified several resting state networks. In order to deepen the understanding of different levels of global brain function from relaxed wakefulness to sleep onset the association between EEG-vigilance stages and BOLD signals was analysed. EEG-vigilance stages were attributed to consecutive 3-sec-EEG-segments by an algorithm using topographic and spectral information. Results of the classification were validated by analysing the heart rates during the different brain states. Vigilance stages served as regressors for the analysis of the simultaneously acquired fMRI data. Additionally resting state networks were derived from the fMRI data using independent component analysis (ICA). Also vigilance associated brain activity revealed by EEG-based standardized low resolution tomography (sLORETA) was compared to the results of the fMRI analysis. Results showed increased BOLD signal in the occipital cortex, the anterior cingulate cortex, the frontal cortex, the parietal cortices and the temporal cortices and decreasing BOLD signals in the thalamus and the frontal cortex for declining vigilance stages (A2, A3, B1, B2/B3) in comparison to the high vigilance stage A1. Resting state networks revealed a spatial overlap with the vigilance stage associated BOLD maps in conjunction analyses. sLORETA showed increased neuroelectric alpha activity at the occipital cortex comparable to occipital BOLD signal decreases when comparing stage A with stage B. Different EEG-vigilance stages during rest are associated with pronounced differences of BOLD signals in several brain areas which partly correspond to the resting state networks. For cognitive fMRI-research it therefore seems important to pay attention to vigilance switches in order to separate vigilance associated BOLD signal changes from those specifically related to cognition.

There is increasing evidence that obsessive-compulsive disorder (OCD) is associated with a dysfunction of cortico-striato-thalamo-cortical neuronal circuits. In order to examine treatment-related changes in neuronal processes, a drug-naive female patient with OCD (subtype: washing/contamination fear) and an age- and gender-matched healthy control were repeatedly tested using functional magnetic resonance imaging (MRI) during the presentation of a symptom provocation task. Patient-specific visual stimuli of symptom provoking situations were compared with disgust provoking and neutral pictures. FMRI scanning was conducted at the beginning, during and upon completion of an inpatient treatment. During the treatment period of more than eight weeks (combined behavioural and systemic couple therapy) the patient filled out a therapy process questionnaire (TPQ) which was administered daily. Results show a phase transition-like change characterized by a sudden reduction of clinical symptoms as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in the middle of the treatment period. Before the discontinuous symptom reduction occurred, the dynamic complexity of the TPQ-time series increased which might be indicative for a critical instability of the system. The fMRI results at the beginning of the treatment suggest strong activities in various brain regions, especially in the anterior cingulate cortex. The results of the second and third acquisition revealed comparably smaller OCD-related neuronal responses. The results may indicate that important clinical changes are taking place during the psychotherapy process which correspond to changing patterns of brain activation as well as to critical instabilities and phase-transition like phenomena in the time-series of the patient's daily self-report data.

While the precise role of the anterior cingulate cortex (ACC) is still being discussed, it has been suggested that ACC activity might reflect the amount of mental effort associated with cognitive processing. So far, not much is known about the temporal dynamics of ACC activity in effort-related decision making or auditory attention, because fMRI is limited concerning its temporal resolution and electroencephalography (EEG) is limited concerning its spatial resolution. Single-trial coupling of EEG and fMRI can be used to predict the BOLD signal specifically related to amplitude variations of electrophysiological components. The striking feature of single-trial coupling is its ability to separate different aspects of the BOLD signal according to their specific relationship to a distinct neural process. In the present study we investigated 10 healthy subjects with a forced choice reaction task under both low and high effort conditions and a control condition (passive listening) using simultaneous EEG and fMRI. We detected a significant effect of mental effort only for the N1 potential, but not for the P300 potential. In the fMRI analysis, ACC activation was present only in the high effort condition. We used single-trial coupling of EEG and fMRI in order to separate information specific to N1-amplitude variations from the unrelated BOLD response. Under high effort conditions we were able to detect circumscribed BOLD activations specific to the N1 potential in the ACC (t=4.7) and the auditory cortex (t=6.1). Comparing the N1-specific BOLD activity of the high effort condition versus the control condition we found only activation of the ACC (random effects analysis, corrected for multiple comparisons, t=4.4). These findings suggest a role of early ACC activation in effort-related decision making and provide a direct link between the N1 component and its corresponding BOLD signal.

Neurophysiological findings such as reduced amplitudes of the P300 potential in patients with schizophrenia are among the most robust findings in biological psychiatry. An enormous literature with findings of abnormal central processing in psychiatric diseases has been acquired during the last decades. However, the benefit of this research has been limited in part due to the unresolved problem of precise and correct localization of the underlying neural generators. The difficulty of correct localization is due to the fact that different constellations of cortical neuroelectric generators can produce identical EEG activity. Therefore, even concerning several major event related potentials no generally accepted knowledge about their cerebral generation exists. While correct localization can easily be obtained by imaging methods based on hemodynamic changes such as functional magnetic resonance imaging (fMRI), these techniques can not distinguish between different aspects of neural activity such as oscillation modes or stages of information processing that are only some milliseconds apart. Accordingly, the integration of simultaneous measurements of EEG and fMRI has become a methodological key issue today. EEG-fMRI may prove to be crucial in providing much deeper understanding of brain activity over the next decades. This review summarizes the basic physiology, methodological issues and interesting applications in psychiatry.

Event related potentials (ERP) are important clinical and research instruments in neuropsychiatry, particularly due to their strategic role for the investigation of brain function. These techniques are often underutilized in the evaluation of neurological and psychiatric disorders, but nevertheless they can be most useful and highly effective in the diagnostic workup of a wide range of neuropsychiatric disorders as well as in monitoring the course of the disorders and the prediction of treatment responses. ERP are noninvasive instruments that directly reflect cortical neuronal activity. Cortical neuronal dysfunction plays a major role in variable neuropsychiatric disorders, and a change in cortical activity under medication might reflect treatment response and could be useful for monitoring drug effects. ERP are the only methods with a sufficiently high time resolution for the analysis of the dynamic patterns of neuronal brain activity, e.g., synchronization and desynchronization, oscillations, coherence, gamma band activity, latency of event related activity, etc., which are crucial for a deeper understanding of functional (neurophysiological) correlates of cognitive, emotional and behavioral disturbances in neuropsychiatric patients. Methodological advances have further improved and strengthened the position of ERP concerning research and clinical application. The usefulness and applicability of ERP in determining and monitoring clinico-pharmacological effects will be summarized mainly by focussing on the auditory evoked P300 and the N1/P2 component of auditory evoked potentials. Owing to important recent developments in the field of brain functional diagnostics the combination of neurophysiological techniques and functional magnetic resonance imaging (fMRI) will be included.

Sound level dependence has been investigated for years with event-related potentials (ERP). A serotonergic modulation of the sound level dependence only of the primary auditory cortex but not of the auditory association cortex has been suggested by a number of clinical and preclinical studies. Therefore, a precise covering of the activity of the primary auditory cortex seems necessary if sound level dependence is used as an indicator of the central serotonergic system. Recent fMRI studies described a pronounced sound level dependence only in the Heschl gyrus/primary auditory cortex but not in auditory association areas. In the present simultaneous 61-channel EEG and fMRI study investigating fourteen healthy subjects, we found a high correlation between the loudness-dependent change of the extent of fMRI activation (number of activated voxels) and the corresponding changes of the mean current source density within the same region of interest covering the primary auditory cortex (r = 0.84, P < 0.001). Our findings suggest a close relationship between the fMRI signal and event-related potential activity. In addition, the correspondence of the ERP-based data and the fMRI results further supports the validity of the ERP localization approach.

fMRI and EEG are complimentary methods for the analysis of brain activity since each method has its strength where the other one has limits: The spatial resolution is thus in the range of millimeters with fMRI and the time resolution is in the range of milliseconds with EEG. For a comprehensive understanding of brain activity in target detection, nine healthy subjects (age 24.2 +/- 2.9) were investigated with simultaneous EEG (27 electrodes) and fMRI using an auditory oddball paradigm. As a first step, event-related potentials, measured inside the scanner, have been compared with the potentials recorded in a directly preceding session in front of the scanner. Attenuated amplitudes were found inside the scanner for the earlier N1/P2 component but not for the late P300 component. Second, an independent analysis of the localizations of the fMRI activations and the current source density as revealed by low resolution electromagnetic tomography (LORETA) has been done. Concordant activations were found in most regions, including the temporoparietal junction (TPJ), the supplementary motor area (SMA)/anterior cingulate cortex (ACC), the insula, and the middle frontal gyrus, with a mean Euclidean distance of 16.0 +/- 6.6 mm between the BOLD centers of gravity and the LORETA-maxima. Finally, a time-course analysis based on the current source density maxima was done. It revealed different time-course patterns in the left and right hemisphere with earlier activations in frontal and parietal regions in the right hemisphere. The results suggest that the combination of EEG and fMRI permits an improved understanding of the spatiotemporal dynamics of brain activity.

Background: Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features. Methods: Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPI bipolar). Results: For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11–0.361) and a balanced accuracy of 63.1% (95% CI 55.9–70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI −0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6–67.8). BARS and EPI bipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance. Conclusions: Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder is one of the most severe mental disorders. Its chronic course is associated with high rates of morbidity and mortality, a high risk of suicide and poor social and occupational outcomes. Despite the great advances over the last decades in understanding mental disorders, the mechanisms underlying bipolar disorder at the neural network level still remain elusive. This has severe consequences for clinical practice, for instance by inadequate diagnoses or delayed treatments. The German research consortium BipoLife aims to shed light on the mechanisms underlying bipolar disorders. It was established in 2015 and incorporates ten university hospitals across Germany. Its research projects focus in particular on individuals at high risk of bipolar disorder, young patients in the early stages of the disease and patients with an unstable highly relapsing course and/or with acute suicidal ideation. Methods: Functional and structural magnetic resonance imaging (MRI) data was acquired across nine sites within three different studies. Obtaining neuroimaging data in a multicenter setting requires among others the harmonization of the acquisition protocol, the standardization of paradigms and the implementation of regular quality control procedures. The present article outlines the MRI imaging protocols, the acquisition parameters, the imaging paradigms, the neuroimaging quality assessment procedures and the number of recruited subjects. Discussion: The careful implementation of a MRI study protocol as well as the adherence to well-defined quality assessment procedures is one key benchmark in the evaluation of the overall quality of large-scale multicenter imaging studies. This article contributes to the BipoLife project by outlining the rationale and the design of the MRI study protocol. It helps to set the necessary standards for follow-up analyses and provides the technical details for an in-depth understanding of follow-up publications. [ABSTRACT FROM AUTHOR]

Background Recent studies using an advanced diffusion model, Free Water Imaging (FWI), have demonstrated that fractional anisotropy (FA) reductions in schizophrenia (SZ) patients were mostly associated with increases in extracellular free-water (FW) in the early stages of the illness, while patients with chronic SZ predominantly showed decreases in FA of the tissue (FAt). Conversely, a study comparing patients with chronic bipolar disorder (BP) and healthy individuals (HC) reported that FW was increased in BP subjects suggesting a different trajectory compared to the one found in SZ patients. The present study is the first to investigate WM properties in adolescent-onset SZ and BP together. Utilizing conventional diffusion tensor imaging and FWI, we aim to identify imaging biomarkers that could help differentiate the biological nature of these two disorders. Methods Forty-eight (20F/28M) SZ patients (mean age: 16.28), 15 (7F/8M) BP patients (mean age: 15.52) and 35 (18F/17M) HCs (mean age: 15.65) were included in the study. The mean duration of psychosis (DOP) was 0.97 years in BP subjects and 1.84 years in SZ subjects. All participants underwent diffusion MRI scanning (1.5 T Siemens Magnetom Sonata, 60 gradient directions with b = 1000 m/s2 and 5 images with b = 0 m/s2). Each scan was repeated three times to increase the signal-to-noise ratio and was subsequently corrected for motion and eddy currents before getting averaged. FA, FAt and FW maps were calculated and then skeletonized using Tract-Based Spatial Statistics (TBSS). Voxel-wise, non-parametric statistics were conducted with 5000 permutations and threshold-free cluster enhancement controlling for age, sex and motion. Statistical maps were family-wise error corrected at a significance level of p < 0.05. Results Significant ANOVA effects were explained by pairwise post-hoc t-tests revealing the expected global FA decrease in SZ and BP subjects comparing to HCs. Further, lower FA restricted to the corpus callosum was found in BP comparing to SZ individuals. Applying FWI, BP subjects had both spatially limited decreased FAt and widespread increased FW comparing with HCs, while SZ subjects had extensively decreased FAt but not increased FW. Comparing between the BP and SZ groups, there was no difference in FAt, but significantly higher FW in BP in most regions of the WM skeleton. Discussion Our results are in line with previous studies suggesting a perturbation of WM health in individuals suffering from BP and SZ. The use of FWI in the present study allows for the further clarification of the biological nature of FA reductions: while SZ patients showed only reductions in FAt compared to HCs, the BP group also had marked increases in FW both compared to HCs and the SZ group. These increases in FW spatially overlapped with FA decreases, suggesting that an extra-cellular pathology is driving the observed FA reductions. The present alterations of WM properties in adolescent-onset BP are similar to those previously described in chronic BP and indicate that FW increases might be a biomarker of BP disorder. Interestingly, the adolescent SZ group, unlike recent-onset or first episode adult SZ cohorts, show no FW alterations, but instead FAt reductions similar to those previously reported in chronic SZ subjects. This could be explained by the longer illness duration, or different disease trajectories between adult and adolescent-onset psychosis. Taken together, we show differential patterns of WM aberrations in adolescent-onset SZ and BP, which lend support to the presence of distinct pathologies underlying the neurobiological development and manifestation of these disorders. [ABSTRACT FROM AUTHOR]

Background Altered gamma-band connectivity has been shown across all stages of schizophrenia (SZ) and for persons at High Risk for Psychosis (HRP). Oscillations in the gamma-band frequency range are suggested to play a crucial role for both local and long-range synchronization within the brain during perceptual and cognitive processes. Structural connectivity in the brain is provided by white matter (WM) tracts connecting these areas. Reduced WM integrity is also a feature of SZ that has often been described. The aim of this study is to investigate the relationship between altered gamma-band connectivity and WM structural connectivity in Clinical High Risk for Psychosis (HRP) patients using Electroencephalography (EEG) and Diffusion Tensor Imaging (DTI) to achieve a better understanding of which factors could predict a transition to SZ considering functional and structural connectivity. The identification of those biomarkers would be a further step toward understanding the causes of SZ and could contribute to a more individualized and targeted therapy to achieve a better outcome in patients. Methods The study includes a total of 26 HRP patients, 7 converted to schizophrenia after one year (HRP-C) and 13 healthy controls (HC). High density EEG (64 channels) was recorded during the performance of a cognitively demanding auditory choice reaction task. Source estimation and analysis of the functional gamma-band connectivity was done using eLORETA. We defined Regions of Interest (ROIs) that were known to be generators of the auditory evoked Gamma-Band Response (aeGBR) from a previous combined EEG-fMRI study of this population – the dorsal anterior cingulate cortex (dACC) and the bilateral auditory cortices. MRI data acquisition was done with a 3T Siemens scanner (Trio). We generated whole-brain 2-Tensor-Tractography for all subjects in order to analyze the integrity of the underlying WM fiber bundles implicated in this functional network, namely the Cingulum Bundle (CB), the Medial Longitudinal Fasciculus (MdLF), the Arcuate Fasciculus (AF) and the Extreme Capsule (EC).The primary outcome measure is the fractional anisotropy of the tissue (FAt), which is corrected for free water (FW) in the brain. Results Our preliminary results show a lower aeGBR in HRP-C patients compared to HC with the HRP-NC at an intermediate level. We found longer reaction times for HRP compared to HC. The study is presently on-going. Based on previous work in this sample, we hypothesize that the CB, MdLF, AF and EC of the HRP-C will exhibit decreased FAt and increased FW compared to HC. Discussion The combination of EEG with its high temporal resolution and DTI with its high spatial resolution allows for detailed insight into the possible disturbances in HRP patients compared to HC. Alterations in both modalities have been shown before, however, in this study we aim to link functional connectivity alterations in the previously described networks to their structural correlate to achieve a better insight into their interaction. Taken together, the quantification of those possible biomarkers might help to detect a transition to SZ earlier and thus allow an early intervention. [ABSTRACT FROM AUTHOR]

CNTNAP2 is a gene on chromosome 7 that has shown associations with autism andschizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p=.00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology.

Background: Alterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD.Methods: Ten individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FAT) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion.Results: The MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FAT in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043).Limitations: The small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD.Conclusions: This pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment. [ABSTRACT FROM AUTHOR]