TMS-evoked potential in the dorsolateral prefrontal cortex to assess the severity of depression disease: a TMS-EEG study.

Objective: The combined use of transcranial magnetic stimulation and electroencephalography (TMS-EEG), as a powerful technique that can non-invasively probe the state of the brain, can be used as a method to study neurophysiological markers in the field of psychiatric disorders and discover potential diagnostic predictors. This study used TMS-evoked potentials (TEPs) to study the cortical activity of patients with major depressive disorder depression (MDD) and the correlation with clinical symptoms to provide an electrophysiological basis for the clinical diagnosis. Methods: A total of 41 patients and 42 healthy controls were recruited to study. Using TMS-EEG techniques to measure the left dorsolateral prefrontal cortex (DLPFC) 's TEP index and evaluate the clinical symptoms of MDD patients using the Hamilton Depression Scale-24 (HAMD-24). Results: MDD subjects performing TMS-EEG on the DLPFC showed lower cortical excitability P60 index levels than healthy controls. Further analysis revealed that the degree of P60 excitability within the DLPFC of MDD patients was significantly negatively correlated with the severity of depression. Conclusion: The low levels of P60 exhibited in DLPFC reflect low excitability in MDD; the P60 component can be used as a biomarker for MDD in clinical assessment tools.

Differential symptom cluster responses to repetitive transcranial magnetic stimulation treatment in depression.

Background: Repetitive transcranial magnetic stimulation (rTMS) can target specific neural circuits, which may allow for personalized treatment of depression. Treatment outcome is typically determined using sum scores from validated measurement scales; however, this may obscure differential improvements within distinct symptom domains. The objectives for this work were to determine: (1) whether a standard depression measure can be represented using a four symptom cluster model and (2) whether these symptom clusters had a differential response to rTMS treatment. Methods: Data were obtained from two multi-centre randomized controlled trials of rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC) for participants with treatment-resistant depression (TRD) conducted in Canada (THREE-D [Conducted between Sept 2013, and Oct 2016] and CARTBIND [Conducted between Apr 2016 and Feb 2018]). The first objective used confirmatory factor analytic techniques, and the second objective used a linear mixed effects model. Trial Registration: NCT01887782, NCT02729792. Findings: In the total sample of 596 participants with TRD, we found a model consisting of four symptom clusters adequately fit the data. The primary analysis using the THREE-D treatment trial found that symptom clusters demonstrated a differential response to rTMS treatment (F(3,5984) = 31.92, p < 0.001). The anxiety symptom cluster was significantly less responsive to treatment than other symptom clusters (t(6001) = -8.02, p < 0.001). These findings were replicated using data from the CARTBIND trial. Interpretation: There are distinct symptom clusters experienced by individuals with TRD that have a differential response to rTMS. Future work will determine whether differing rTMS treatment targets have distinct patterns of symptom cluster responses with the eventual goal of personalizing rTMS protocols based on an individual's clinical presentation. Funding: Canadian Institutes of Health Research, Brain Canada.

Effects of transcranial direct current stimulation on neural activity and functional connectivity during fear extinction.

Background/Objective: Anxiety disorders are highly prevalent and negatively impact daily functioning and quality of life. Transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex (dlPFC), especially in the right hemisphere impacts extinction learning; however, the underlying neural mechanisms are elusive. Therefore, we aimed to investigate the effects of cathodal tDCS stimulation to the right dlPFC on neural activity and connectivity patterns during delayed fear extinction in healthy participants. Methods: We conducted a two-day fear conditioning and extinction procedure. On the first day, we collected fear-related self-reports, clinical questionnaires, and skin conductance responses during fear acquisition. On the second day, participants in the tDCS group (n = 16) received 20-min offline tDCS before fMRI and then completed the fear extinction session during fMRI. Participants in the control group (n = 18) skipped tDCS and directly underwent fMRI to complete the fear extinction procedure. Whole-brain searchlight classification and resting-state functional connectivity analyses were performed. Results: Whole-brain searchlight classification during fear extinction showed higher classification accuracy of threat and safe cues in the left anterior dorsal and ventral insulae and hippocampus in the tDCS group than in the control group. Functional connectivity derived from the insula with the dlPFC, ventromedial prefrontal cortex, and inferior parietal lobule was increased after tDCS. Conclusion: tDCS over the right dlPFC may function as a primer for information exchange among distally connected areas, thereby increasing stimulus discrimination. The current study did not include a sham group, and one participant of the control group was not randomized. Therefore, to address potential allocation bias, findings should be confirmed in the future with a fully randomized and sham controlled study.

The effects of a 15-week physical exercise intervention on pain modulation in fibromyalgia: Increased pain-related processing within the cortico-striatal- occipital networks, but no improvement of exercise-induced hypoalgesia.

Dysfunctional top-down pain modulation is a hallmark of fibromyalgia (FM) and physical exercise is a cornerstone in FM treatment. The aim of this study was to explore the effects of a 15-week intervention of strengthening exercises, twice per week, supervised by a physiotherapist, on exercise-induced hypoalgesia (EIH) and cerebral pain processing in FM patients and healthy controls (HC). FM patients (n = 59) and HC (n = 39) who completed the exercise intervention as part of a multicenter study were examined at baseline and following the intervention. Following the exercise intervention, FM patients reported a reduction of pain intensity, fibromyalgia severity and depression. Reduced EIH was seen in FM patients compared to HC at baseline and no improvement of EIH was seen following the 15-week resistance exercise intervention in either group. Furthermore, a subsample (Stockholm site: FM n = 18; HC n = 19) was also examined with functional magnetic resonance imaging (fMRI) during subjectively calibrated thumbnail pressure pain stimulations at baseline and following intervention. A significant main effect of exercise (post > pre) was observed both in FM patients and HC, in pain-related brain activation within left dorsolateral prefrontal cortex and caudate, as well as increased functional connectivity between caudate and occipital lobe bordering cerebellum (driven by the FM patients). In conclusion, the results indicate that 15-week resistance exercise affect pain-related processing within the cortico-striatal-occipital networks (involved in motor control and cognition), rather than directly influencing top-down descending pain inhibition. In alignment with this, exercise-induced hypoalgesia remained unaltered.

Effect of Cognition Recovery by Repetitive Transcranial Magnetic Stimulation on Ipsilesional Dorsolateral Prefrontal Cortex in Subacute Stroke Patients.

OBJECTIVE: To demonstrate the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the ipsilesional dorsolateral prefrontal cortex (DLPFC) on neurological recovery in patients with subacute phase stroke. METHODS: Patients with supratentorial hemispheric stroke who were hospitalized for intensive rehabilitation in the subacute phase were enrolled for this retrospective analysis. Two groups of patients were selected: the rTMS group who received high-frequency (20 Hz) rTMS ≥ 5 times over the ipsilesional DLPFC, and a control group who did not receive any rTMS. The patients were further divided into groups with right- or left-side brain lesions. Functional measurements for cognitive ability, mood, speech, and activities of daily living, which were assessed at baseline and at the 1-month follow-up as a routine clinical practice, were used for analyses. RESULTS: Among 270 patients with available clinical data, 133 (women, 51; age, 61.0 ± 13.8 years) met the inclusion criteria and were enrolled for analysis. There were no differences in demographic data and functional scores at baseline between the rTMS (n = 49) and control (n = 84) groups. The rTMS group showed a higher gain in the mini-mental status examination (MMSE) total score and subscores of all domains, forward digit span, and FIM-cognition than the control group (P < 0.05). Among the patients with left hemispheric lesions (n = 57), the rTMS group showed better outcomes in cognition and depression through scores of total and "attention and concentration" subscores of MMSE, FIM-cognition, and the geriatric depression scale (P < 0.05). Among the patients with right hemispheric lesions (n = 76), the rTMS group showed better outcomes in cognition through the MMSE total score and subscores of "attention and concentration," "registration," and "recall," and scores of both forward and backward digit spans (P < 0.05). CONCLUSION: High-frequency rTMS over the ipsilesional DLPFC has beneficial effects on the recovery of cognition on both sides as well as mood in patients with left-sided hemispheric lesions.

Baseline Clinical and Neuroimaging Biomarkers of Treatment Response to High-Frequency rTMS Over the Left DLPFC for Resistant Depression.

Background: Repetitive transcranial magnetic stimulation (rTMS) has proven to be an efficient treatment option for patients with treatment-resistant depression (TRD). However, the success rate of this method is still low, and the treatment outcome is unpredictable. The objective of this study was to explore clinical and structural neuroimaging factors as potential biomarkers of the efficacy of high-frequency (HF) rTMS (20 Hz) over the left dorso-lateral pre-frontal cortex (DLPFC). Methods: We analyzed the records of 131 patients with mood disorders who were treated with rTMS and were assessed at baseline at the end of the stimulation and at 1 month after the end of the treatment. The response is defined as a 50% decrease in the MADRS score between the first and the last assessment. Each of these patients underwent a T1 MRI scan of the brain, which was subsequently segmented with FreeSurfer. Whole-brain analyses [Query, Design, Estimate, Contrast (QDEC)] were conducted and corrected for multiple comparisons. Additionally, the responder status was also analyzed using binomial multivariate regression models. The explored variables were clinical and anatomical features of the rTMS target obtained from T1 MRI: target-scalp distance, DLPFC gray matter thickness, and various cortical measures of interest previously studied. Results: The results of a binomial multivariate regression model indicated that depression type (p = 0.025), gender (p = 0.010), and the severity of depression (p = 0.027) were found to be associated with response to rTMS. Additionally, the resistance stage showed a significant trend (p = 0.055). Whole-brain analyses on volume revealed that the average volume of the left part of the superior frontal and the caudal middle frontal regions is associated with the response status. Other MRI-based measures are not significantly associated with response to rTMS in our population. Conclusion: In this study, we investigated the clinical and neuroimaging biomarkers associated with responsiveness to high-frequency rTMS over the left DLPFC in a large sample of patients with TRD. Women, patients with bipolar depressive disorder (BDD), and patients who are less resistant to HF rTMS respond better. Responders present a lower volume of the left part of the superior frontal gyrus and the caudal middle frontal gyrus. These findings support further investigation into the use of clinical variables and structural MRI as possible biomarkers of rTMS treatment response.

Relationship between psychosocial stress-induced prefrontal cortex activity and gut microbiota in healthy Participants-A functional near-infrared spectroscopy study.

Brain and gut microbes communicate in a bidirectional manner with each affecting a person's response to psychosocial stress. Although human studies demonstrated that the intake of probiotics can alter stress-related behavior in both patients and healthy participants, the association between stress-related brain functions and the gut microbiota has mostly been investigated in patients with depression. However, the response to psychosocial stress differs, even among healthy individuals, and elucidating the natural state of the gut microbiota would broaden the understanding of responses to psychosocial stress. We investigated the relationship between psychosocial stress response in the prefrontal cortex and the abundance of gut microbes in healthy male participants. The participants were exposed to psychosocial stress during a task while brain activation data were recorded using functional near-infrared spectroscopy. The heart rate and subjective stress were recorded, and fecal samples were collected. The stressful condition was accompanied by high subjective stress, high heart rate, and higher prefrontal activation in the right pre-motor cortex/supplementary motor area, right dorsolateral prefrontal cortex, right frontal pole, and right inferior prefrontal gyrus. The psychosocial stress response in the prefrontal cortex was also associated with changes in the gut microbiota abundance. The abundance of Alistipes, Clostridium IV, Clostridium XI, Faecalibacterium, and Blautia in healthy participants who had high psychosocial stress resembled that noted in patients with depression. These results suggest that the gut microbiota differs, among healthy participants, depending on the psychosocial stress response. We believe that this study is the first to report a direct relationship between brain function and the gut microbiota in healthy participants, and our findings would shed a new light on this field in the near future.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Investigating Cortical Buffering Effects of Acute Moderate Intensity Exercise: A cTBS Study Targeting the Left Dorsolateral Prefrontal Cortex.

Background: The beneficial effects of both single-session bouts of aerobic exercise and therapeutic exercise interventions on the cortical regions associated with top-down attentional control [i.e., prefrontal cortex (PFC)] have been well documented. However, it remains unclear whether aerobic exercise can be used to buffer against suppressive influences on the dorsolateral PFC (dlPFC). Objective: The current study sought to determine whether a single session of moderate intensity aerobic exercise can offset the expected suppressive effects of continuous theta burst stimulation (cTBS) targeting the dorsolateral prefrontal cortex (dlPFC). Methods: Twenty-two right-handed participants (aged 19-30) completed a 20-minute movement-only control session [10% heart rate reserve (HRR)] and moderate intensity (50% HRR) exercise in a counterbalanced order. Following each exercise session, participants received active cTBS to the left dlPFC. Changes in executive functions were quantified using a Flanker paradigm employed at baseline, post-exercise and post-cTBS time points. Additionally, EEG was used to measure changes in event-related potential components related to inhibitory control (i.e., N2) and attentional control (i.e., P3) during the flanker task. Results: Behavioral results from the flanker task revealed a significant improvement in task performance following an acute bout of moderate intensity exercise. Furthermore, the effect of cTBS in both the movement-only control and moderate intensity conditions were non-significant. Similarly, EEG data from P3b and N2 ERP components revealed no changes to amplitude across time and condition. P3b latency data revealed a significant effect of time in both the moderate intensity and movement-only conditions, such that P3b latencies were significantly shorter across time points. Latency data within the N2 ERP component revealed no significant interactions or main effects. Conclusion: The findings of the current study provide tentative support for the hypothesis that both moderate and light intensity exercise promote cortical buffering against the suppressive effects of cTBS targeting the dlPFC. However, in the absence of a no-movement control, a lack of expected suppressive effects of cTBS cannot be ruled out.

Potential Locations for Non-Invasive Brain Stimulation in Treating Schizophrenia: A Resting-State Functional Connectivity Analysis.

Introduction: Non-invasive brain stimulation (NIBS) techniques have been widely used for the purpose of improving clinical symptoms of schizophrenia. However, the ambiguous stimulation targets may limit the efficacy of NIBS for schizophrenia. Exploring effective stimulation targets may improve the clinical efficacy of NIBS in schizophrenia. Methods: We first conducted a neurosynth-based meta-analysis of 715 functional magnetic resonance imaging studies to identify schizophrenia-related brain regions as regions of interest. Then, we performed the resting-state functional connectivity analysis in 32 patients with first-episode schizophrenia to find brain surface regions correlated with the regions of interest in three pipelines. Finally, the 10-20 system coordinates corresponding to the brain surface regions were considered as potential targets for NIBS. Results: We identified several potential targets of NIBS, including the bilateral dorsal lateral prefrontal cortex, supplementary motor area, bilateral inferior parietal lobule, temporal pole, medial prefrontal cortex, precuneus, superior and middle temporal gyrus, and superior and middle occipital gyrus. Notably, the 10-20 system location of the bilateral dorsal lateral prefrontal cortex was posterior to F3 (F4), not F3 (F4). Conclusion: Conclusively, our findings suggested that the stimulation locations corresponding to these potential targets might help clinicians optimize the application of NIBS therapy in individuals with schizophrenia.

Disrupted hemispheric connectivity specialization in patients with major depressive disorder: Evidence from the REST-meta-MDD Project.

BACKGROUND: Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied. METHODS: Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes). RESULTS: Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities. LIMITATIONS: Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results. CONCLUSIONS: Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective.

Twice-Daily Theta Burst Stimulation of the Dorsolateral Prefrontal Cortex Reduces Methamphetamine Craving: A Pilot Study.

OBJECTIVES: Transcranial magnetic stimulation (TMS) holds potential promise as a therapeutic modality for disorders of addiction. Our previous findings indicate that high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsal-lateral prefrontal cortex (DLPFC) and low-frequency rTMS over the right DLPFC can reduce drug craving for methamphetamine. One major issue with rTMS is the duration of treatment and hence potential dropout rate. Theta burst stimulation (TBS) has been recently shown to be non-inferior relative to repetitive transcranial magnetic stimulation for major depression. Here, we aim to compare the clinical efficacy and tolerability of intermittent and continuous theta burst stimulation protocols targeting left or right dorsolateral prefrontal cortex on methamphetamine craving in abstinent-dependent subjects. METHODS: In this randomized single-blind pilot study, 83 abstinent methamphetamine-dependent subjects from a long-term residential treatment program were randomly allocated into three groups: intermittent theta burst stimulation (iTBS) over the left DLPFC (active group), continuous theta burst stimulation (cTBS) over the left DLPFC (active control group), or cTBS over the right DLPFC (active group) was administered twice daily over 5 days for a total of 10 sessions. We measured the primary outcome of cue-induced craving and secondarily sleep quality, depression, anxiety, impulsivity scores, and adverse effects. RESULTS: We show a pre- vs. postintervention effect on craving, which, on paired t tests, showed that the effect was driven by iTBS of the left DLPFC and cTBS of the right DLPFC, reducing cue-induced craving but not cTBS of the left DLPFC. We did not show the critical group-by-time interaction. The secondary outcomes of depression, anxiety, and sleep were unrelated to the improvement in craving in the left iTBS and right cTBS group. In the first two sessions, self-reported adverse effects were higher with left iTBS when compared to right cTBS. The distribution of craving change suggested greater clinical response (50% improvement) with right cTBS and a bimodal pattern of effect with left iTBS, suggesting high interindividual variable response in the latter. CONCLUSION: Accelerated twice-daily TBS appears feasible and tolerable at modulating craving and mood changes in abstinent methamphetamine dependence critically while reducing session length. We emphasize the need for a larger randomized controlled trial study with a sham control to confirm these findings and longer duration of clinically relevant follow-up. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry number, 17013610.

Modulation of Emotional Conflict Processing by High-Definition Transcranial Direct Current Stimulation (HD-TDCS).

Cognitive control is characterized by selective attention to relevant stimuli while irrelevant, distracting stimuli are inhibited. While the classical color-word Stroop task was implemented to investigate the processes of cognitive control, a variant of it-the face-word Stroop task-allows for directly investigating processes of emotional conflict control. It is thought that the prefrontal cortex (PFC) is especially involved in processes of cognitive control, while the rostral cingulate is mainly associated with the resolution of emotional conflict. In recent years, the role of the dorsolateral PFC (DLPFC) during the performance of the classical Stroop was investigated by means of transcranial direct current stimulation (tDCS) with divergent results. However, investigations to the causal role of the DLPFC during emotional conflict processing are rare. For this purpose, we used a combined high-definition tDCS (HD-tDCS)/electroencephalogram (EEG) setting to investigate the impact of anodal stimulation of the left DLPFC on behavioral and electrophysiological responses during an emotional face-word Stroop task. In two separate sessions, participants (n = 18) received either sham or anodal HD-tdc stimulation while responding to the emotional expression of the face and ignoring the word. Our results show that anodal stimulation of the left DLPFC increases the behavioral interference effect, that is, the already decelerated reaction times (RTs) to incongruent trials further increase while RTs to congruent trials remain largely unaffected. Furthermore, the stimulation modulates brain response to emotional facial expressions during the face-word Stroop generally-independent of the valence of the emotional expression and the congruency of the combined face-word presentation, the N170 decreases during anodal stimulation. These results reveal that the left DLPFC has a causal role in emotional conflict processing during a face-word Stroop.

Effects of in-Scanner Bilateral Frontal tDCS on Functional Connectivity of the Working Memory Network in Older Adults.

Working memory is an executive memory process essential for everyday decision-making and problem solving that declines with advanced age. Transcranial direct current stimulation (tDCS) is a non-invasive form of brain stimulation that has demonstrated potential for improving working memory performance in older adults. However, the neural mechanisms underlying effects of tDCS on working memory are not well understood. This mechanistic study investigated the acute and after-effects of bilateral frontal (F3/F4) tDCS at 2 mA for 12-min on functional connectivity of the working memory network in older adults. We hypothesized active tDCS over sham would increase frontal connectivity during working memory performance. The study used a double-blind within-subject 2 session crossover design. Participants performed an functional magnetic resonance imaging (fMRI) N-Back working memory task before, during, and after active or sham stimulation. Functional connectivity of the working memory network was assessed within and between stimulation conditions (FDR < 0.05). Active tDCS produced a significant increase in functional connectivity between left ventrolateral prefrontal cortex (VLPFC) and left dorsolateral PFC (DLPFC) during stimulation, but not after stimulation. Connectivity did not significantly increase with sham stimulation. In addition, our data demonstrated both state-dependent and time-dependent effects of tDCS working memory network connectivity in older adults. tDCS during working memory performance produces a selective change in functional connectivity of the working memory network in older adults. These data provide important mechanistic insight into the effects of tDCS on brain connectivity in older adults, as well as key methodological considerations for tDCS-working memory studies.

Common and distinct abnormal frontal-limbic system structural and functional patterns in patients with major depression and bipolar disorder.

Major depressive disorder (MDD) and bipolar disorder (BD) are common severe affective diseases. Although previous neuroimaging studies have investigated brain abnormalities in MDD or BD, the structural and functional differences between these two disorders remain unclear. In this study, we adopted a multimodal approach, combining voxel-based morphometry (VBM) and functional connectivity (FC), to study the common and distinct structural and functional alterations in unmedicated MDD and BD patients. The VBM analysis revealed that both the MDD and BD patients showed decreased gray matter volume (GMV) in the left anterior cingulate cortex (ACC_L) and right hippocampus (HIP_R) compared with the healthy controls, and the MDD patients showed decreased GMV in the left superior frontal gyrus (SFG_L) and ACC_L compared with the BD patients. Furthermore, we took these clusters as seed regions to analyze the abnormal resting-state functional connectivity (RSFC) in the patients. We found that both the MDD and BD groups had decreased RSFC between the ACC_L and the left orbitofrontal cortex (OFC_L) and that the MDD group had decreased RSFC between the SFG_L and the HIP_L, compared with the healthy controls. Our results revealed that the MDD and BD patients were more similar than different in GMV and RSFC. These findings indicate that investigating the frontal-limbic system could be useful for understanding the underlying mechanisms of these two disorders.

Cortical arousal in children and adolescents with functional neurological symptoms during the auditory oddball task.

OBJECTIVE: Stress, pain, injury, and psychological trauma all induce arousal-mediated changes in brain network organization. The associated, high level of arousal may disrupt motor-sensory processing and result in aberrant patterns of motor function, including functional neurological symptoms. We used the auditory oddball paradigm to assess cortical arousal in children and adolescents with functional neurological symptom disorder. METHOD: Electroencephalogram (EEG) data was collected in fifty-seven children and adolescents (41 girls; 16 boys, aged 8.5-18 years) with acute functional neurological symptoms and age- sex- matched controls during a conventional auditory oddball task. The high-resolution fragmentary decomposition technique was used to analyse the amplitude of event-related potentials (ERPs) to target tones at midline sites (Fz, Cz, and Pz). RESULTS: Compared to age- and sex-matched controls, and across all three midline sites, children and adolescents with functional neurological symptoms showed increased amplitude of all ERP components (P50, N100, P200, N200, and P300) (t-value range 2.28-8.20; p value-range 0.023 to < 0.001) to the emotionally-neutral auditory stimulus. CONCLUSIONS: Our findings add to a growing literature indicating that a baseline state of high arousal may be a precondition for generating functional neurological symptoms, a finding that helps explain why a range of psychological and physiological stressors can trigger functional neurological symptoms in some patients. Interventions that target cortical arousal may be central to the treatment of paediatric patients with functional neurological symptom disorder.

Brain responses to vestibular pain and its anticipation in women with Genito-Pelvic Pain/Penetration Disorder.

OBJECTIVE: In DSM-5, pain-related fear during anticipation of vaginal penetration is a diagnostic criterion of Genito-Pelvic Pain/Penetration Disorder (GPPPD). We aimed to investigate subjective and brain responses during anticipatory fear and subsequent induction of vestibular pain in women with GPPPD. METHODS: Women with GPPPD (n = 18) and age-matched healthy controls (HC) (n = 15) underwent fMRI scanning during vestibular pain induction at individually titrated pain threshold after a cued anticipation period. (Pain-related) fear and anxiety traits were measured with questionnaires prior to scanning, and anticipatory fear and pain intensity were rated during scanning using visual analog scales. RESULTS: Women with GPPPD reported significantly higher levels of anticipatory fear and pain intensity. During anticipation and pain induction they had stronger and more extensive brain responses in regions involved in cognitive and affective aspects of pain perception, but the group difference did not reach significance for the anticipation condition. Pain-related fear and anxiety traits as well as anticipatory fear ratings were positively associated with pain ratings in GPPPD, but not in HC. Further, in HC, a negative association was found between anticipatory fear ratings and brain responses in regions involved in cognitive and affective aspects of pain perception, but not in women with GPPPD. CONCLUSIONS: Women with GPPPD are characterized by increased subjective and brain responses to vestibular pain and, to a lesser extent, its anticipation, with fear and anxiety associated with responses to pain, supporting the introduction of anticipatory fear as a criterion of GPPPD in DSM-5.

Neural circuit of verbal humor comprehension in schizophrenia - an fMRI study.

Individuals with schizophrenia exhibit problems with understanding the figurative meaning of language. This study evaluates neural correlates of diminished humor comprehension observed in schizophrenia. The study included chronic schizophrenia (SCH) outpatients (n = 20), and sex, age and education level matched healthy controls (n = 20). The fMRI punchline based humor comprehension task consisted of 60 stories of which 20 had funny, 20 nonsensical and 20 neutral (not funny) punchlines. After the punchlines were presented, the participants were asked to indicate whether the story was comprehensible and how funny it was. Three contrasts were analyzed in both groups reflecting stages of humor processing: abstract vs neutral stories - incongruity detection; funny vs abstract - incongruity resolution and elaboration; and funny vs neutral - complete humor processing. Additionally, parametric modulation analysis was performed using both subjective ratings separately. Between-group comparisons revealed that the SCH subjects had attenuated activation in the right posterior superior temporal gyrus (BA 41) in case of irresolvable incongruity processing of nonsensical puns; in the left dorsomedial middle and superior frontal gyri (BA 8/9) in case of incongruity resolution and elaboration processing of funny puns; and in the interhemispheric dorsal anterior cingulate cortex (BA 24) in case of complete processing of funny puns. Additionally, during comprehensibility ratings the SCH group showed a suppressed activity in the left dorsomedial middle and superior frontal gyri (BA 8/9) and revealed weaker activation during funniness ratings in the left dorsal anterior cingulate cortex (BA 24). Interestingly, these differences in the SCH group were accompanied behaviorally by a protraction of time in both types of rating responses and by indicating funny punchlines less comprehensible. Summarizing, our results indicate neural substrates of humor comprehension processing impairments in schizophrenia, which is accompanied by fronto-temporal hypoactivation.

Age associations with neural processing of reward anticipation in adolescents with bipolar disorders.

Reward/behavioral approach system hypersensitivity is implicated in bipolar disorders (BD) and in normative development during adolescence. Pediatric onset of BD is associated with a more severe illness course. However, little is known about neural processing of rewards in adolescents with BD or developmental (i.e., age) associations with activation of these neural systems. The present study aims to address this knowledge gap. The present sample included 21 adolescents with BD and 26 healthy adolescents, ages 13 to 19. Participants completed a functional magnetic resonance imaging (fMRI) protocol using the Monetary Incentive Delay (MID) task. Behavioral performance was similar between groups. Group differences in BOLD activation during target anticipation and feedback anticipation periods of the task were examined using whole-brain analyses, as were group differences in age effects. During both target anticipation and feedback anticipation, adolescents with BD, compared to adolescents without psychopathology, exhibited decreased engagement of frontal regions involved in cognitive control (i.e., dorsolateral prefrontal cortex). Healthy adolescents exhibited age-related decreases, while adolescents with BD exhibited age-related increases, in activity of other cognitive control frontal areas (i.e., right inferior frontal gyrus), suggesting altered development in the BD group. Longitudinal research is needed to examine potentially abnormal development of cognitive control during reward pursuit in adolescent BD and whether early therapeutic interventions can prevent these potential deviations from normative development.

Neurostructural abnormalities associated with axes of emotion dysregulation in generalized anxiety.

BACKGROUND: Despite the high prevalence of generalized anxiety disorder (GAD) and its negative impact on society, its neurobiology remains obscure. This study characterizes the neurostructural abnormalities associated with key symptoms of GAD, focusing on indicators of impaired emotion regulation (excessive worry, poor concentration, low mindfulness, and physiological arousal). METHODS: These domains were assessed in 19 (16 women) GAD patients and 19 healthy controls matched for age and gender, using questionnaires and a low demand behavioral task performed before and after an induction of perseverative cognition (i.e. worry and rumination). Continuous pulse oximetry was used to measure autonomic physiology (heart rate variability; HRV). Observed cognitive and physiological changes in response to the induction provided quantifiable data on emotional regulatory capacity. Participants underwent structural magnetic resonance imaging; voxel-based morphometry was used to quantify the relationship between gray matter volume and psychological and physiological measures. RESULTS: Overall, GAD patients had lower gray matter volume than controls within supramarginal, precentral, and postcentral gyrus bilaterally. Across the GAD group, increased right amygdala volume was associated with prolonged reaction times on the tracking task (indicating increased attentional impairment following the induction) and lower scores on the 'Act with awareness' subscale of the Five Facets Mindfulness Questionnaire. Moreover in GAD, medial frontal cortical gray matter volume correlated positively with the 'Non-react mindfulness' facet. Lastly, smaller volumes of bilateral insula, bilateral opercular cortex, right supramarginal and precentral gyri, anterior cingulate and paracingulate cortex predicted the magnitude of autonomic change following the induction (i.e. a greater decrease in HRV). CONCLUSIONS: Results distinguish neural structures associated with impaired capacity for cognitive, attentional and physiological disengagement from worry, suggesting that aberrant competition between these levels of emotional regulation is intrinsic to symptom expression in GAD.