Correction: Electronic Health Record-Nested Reminders for Serum Lithium Level Monitoring in Patients With Mood Disorder: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/40595.].

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Association between enhanced carbonyl stress and decreased apparent axonal density in schizophrenia by multimodal white matter imaging.

Carbonyl stress is a condition featuring increased rich reactive carbonyl compounds, which facilitate the formation of advanced glycation end products including pentosidine. We previously reported the relationship between enhanced carbonyl stress and disrupted white matter integrity in schizophrenia, although which microstructural component is disrupted remained unclear. In this study, 32 patients with schizophrenia (SCZ) and 45 age- and gender-matched healthy volunteers (HC) were recruited. We obtained blood samples for carbonyl stress markers (plasma pentosidine and serum pyridoxal) and multi-modal magnetic resonance imaging measures of white matter microstructures including apparent axonal density (intra-cellular volume fraction (ICVF)) and orientation (orientation dispersion index (ODI)), and inflammation (free water (FW)). In SCZ, the plasma pentosidine level was significantly increased. Group comparison revealed that mean white matter values were decreased for ICVF, and increased for FW. We found a significant negative correlation between the plasma pentosidine level and mean ICVF values in SCZ, and a significant negative correlation between the serum pyridoxal level and mean ODI value in HC, regardless of age. Our results suggest an association between enhanced carbonyl stress and axonal abnormality in SCZ.

Distinctive alterations in the mesocorticolimbic circuits in various psychiatric disorders.

AIM: Increasing evidence suggests that psychiatric disorders are linked to alterations in the mesocorticolimbic dopamine-related circuits. However, the common and disease-specific alterations remain to be examined in schizophrenia (SCZ), major depressive disorder (MDD), and autism spectrum disorder (ASD). Thus, this study aimed to examine common and disease-specific features related to mesocorticolimbic circuits. METHODS: This study included 555 participants from four institutes with five scanners: 140 individuals with SCZ (45.0% female), 127 individuals with MDD (44.9%), 119 individuals with ASD (15.1%), and 169 healthy controls (HC) (34.9%). All participants underwent resting-state functional magnetic resonance imaging. A parametric empirical Bayes approach was adopted to compare estimated effective connectivity among groups. Intrinsic effective connectivity focusing on the mesocorticolimbic dopamine-related circuits including the ventral tegmental area (VTA), shell and core parts of the nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) were examined using a dynamic causal modeling analysis across these psychiatric disorders. RESULTS: The excitatory shell-to-core connectivity was greater in all patients than in the HC group. The inhibitory shell-to-VTA and shell-to-mPFC connectivities were greater in the ASD group than in the HC, MDD, and SCZ groups. Furthermore, the VTA-to-core and VTA-to-shell connectivities were excitatory in the ASD group, while those connections were inhibitory in the HC, MDD, and SCZ groups. CONCLUSION: Impaired signaling in the mesocorticolimbic dopamine-related circuits could be an underlying neuropathogenesis of various psychiatric disorders. These findings will improve the understanding of unique neural alternations of each disorder and will facilitate identification of effective therapeutic targets.

Aberrant Large-Scale Network Interactions Across Psychiatric Disorders Revealed by Large-Sample Multi-Site Resting-State Functional Magnetic Resonance Imaging Datasets.

BACKGROUND AND HYPOTHESIS: Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders. STUDY DESIGN: We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network. STUDY RESULTS: DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively. CONCLUSIONS: DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders.

Electronic Health Record-Nested Reminders for Serum Lithium Level Monitoring in Patients With Mood Disorder: Randomized Controlled Trial.

BACKGROUND: Clinical guidelines recommend regular serum lithium monitoring every 3 to 6 months. However, in the real world, only a minority of patients receive adequate monitoring. OBJECTIVE: This study aims to examine whether the use of the electronic health record (EHR)-nested reminder system for serum lithium monitoring can help achieve serum lithium concentrations within the therapeutic range for patients on lithium maintenance therapy. METHODS: We conducted an unblinded, single-center, EHR-nested, parallel-group, superiority randomized controlled trial comparing EHR-nested reminders with usual care in adult patients receiving lithium maintenance therapy for mood disorders. The primary outcome was the achievement of therapeutically appropriate serum lithium levels between 0.4 and 1.0 mEq/L at 18 months after enrollment. The key secondary outcomes are included as follows: the number of serum lithium level monitoring except for the first and final monitoring; exacerbation of the mood disorder during the study period, defined by hospitalization, increase in lithium dose, addition of antipsychotic drugs or mood stabilizers, or addition or increase of antidepressants; adherence defined by the proportion of days covered by lithium carbonate prescription during the study period. RESULTS: A total of 111 patients were enrolled in this study. A total of 56 patients were assigned to the reminder group, and 55 patients were assigned to the usual care group. At the follow-up, 38 (69.1%) patients in the reminder group and 33 (60.0%) patients in the usual care group achieved the primary outcome (odds ratio 2.14, 95% CI 0.82-5.58, P=.12). The median number of serum lithium monitoring was 2 in the reminder group and 0 in the usual care group (rate ratio 3.62; 95% CI 2.47-5.29, P<.001). The exacerbation of mood disorders occurred in 17 (31.5%) patients in the reminder group and in 16 (34.8%) patients in the usual care group (odds ratio 0.97, 95% CI 0.42-2.28, P=.95). CONCLUSIONS: We found insufficient evidence for an EHR-nested reminder to increase the achievement of therapeutic serum lithium concentrations. However, the number of monitoring increased with relatively simple and inexpensive intervention. The EHR-based reminders may be useful to improve quality of care for patients on lithium maintenance therapy, and they have potentials to be applied to other problems. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000033633; https://tinyurl.com/5n7wtyav.

Depressive symptoms reduce when dorsolateral prefrontal cortex-precuneus connectivity normalizes after functional connectivity neurofeedback.

Depressive disorders contribute heavily to global disease burden; This is possibly because patients are often treated homogeneously, despite having heterogeneous symptoms with differing underlying neural mechanisms. A novel treatment that can directly influence the neural circuit relevant to an individual patient's subset of symptoms might more precisely and thus effectively aid in the alleviation of their specific symptoms. We tested this hypothesis in a proof-of-concept study using fMRI functional connectivity neurofeedback. We targeted connectivity between the left dorsolateral prefrontal cortex/middle frontal gyrus and the left precuneus/posterior cingulate cortex, because this connection has been well-established as relating to a specific subset of depressive symptoms. Specifically, this connectivity has been shown in a data-driven manner to be less anticorrelated in patients with melancholic depression than in healthy controls. Furthermore, a posterior cingulate dominant state-which results in a loss of this anticorrelation-is expected to specifically relate to an increase in rumination symptoms such as brooding. In line with predictions, we found that, with neurofeedback training, the more a participant normalized this connectivity (restored the anticorrelation), the more related (depressive and brooding symptoms), but not unrelated (trait anxiety), symptoms were reduced. Because these results look promising, this paradigm next needs to be examined with a greater sample size and with better controls. Nonetheless, here we provide preliminary evidence for a correlation between the normalization of a neural network and a reduction in related symptoms. Showing their reproducibility, these results were found in two experiments that took place several years apart by different experimenters. Indicative of its potential clinical utility, effects of this treatment remained one-two months later.Clinical trial registration: Both experiments reported here were registered clinical trials (UMIN000015249, jRCTs052180169).

Atypical spatial frequency dependence of visual metacognition among schizophrenia patients.

Although altered early stages of visual processing have been reported among schizophrenia patients, how such atypical visual processing may affect higher-level cognition remains largely unknown. Here we tested the hypothesis that metacognitive performance may be atypically modulated by spatial frequency (SF) of visual stimuli among individuals with schizophrenia, given their altered magnocellular function. To study the effect of SF on metacognitive performance, we asked patients and controls to perform a visual detection task on gratings with different SFs and report confidence, and analyzed the data using the signal detection theoretic measure meta-d'. Control subjects showed better metacognitive performance after yes- (stimulus presence) than after no- (stimulus absence) responses ('yes-response advantage') for high SF (HSF) stimuli but not for low SF (LSF) stimuli. The patients, to the contrary, showed a 'yes-response advantage' not only for HSF but also for LSF stimuli, indicating atypical SF dependency of metacognition. An fMRI experiment using the same task revealed that the dorsolateral prefrontal cortex (DLPFC), known to be crucial for metacognition, shows activity mirroring the behavioral results: decoding accuracy of perceptual confidence in DLPFC was significantly higher for HSF than for LSF stimuli in controls, whereas this decoding accuracy was independent of SF in patients. Additionally, the functional connectivity of DLPFC with parietal and visual areas was modulated by SF and response type (yes/no) in a different manner between controls and patients. While individuals without schizophrenia may flexibly adapt metacognitive computations across SF ranges, patients may employ a different mechanism that is independent of SF. Because visual stimuli of low SF have been linked to predictive top-down processing, this may reflect atypical functioning in these processes in schizophrenia.

Relationships between types of esophagogastric varices and systemic hemodynamics in patients with liver cirrhosis.

BACKGROUND/AIMS: To investigate the relationships between the types of esophagogastric varices and systemic hemodynamics in patients with liver cirrhosis. METHODOLOGY: Fifty-three patients with esophagogastric varices were included in this study and divided into 4 groups according esophagogastric varices type. Groups 1 and 2 were medium-size (F2-EV) and large-size esophageal varices (F3-EV), respectively. Groups 3 and 4 were medium-size (F2-GV) and large-size isolated gastric varices (F3-GV), respectively. RESULTS: The cardiac indexes (CI) were 3.61 +/- 0.76, 4.65 +/- 1.11, 3.78 +/- 0.69 and 4.65 +/- 0.75 in groups 1 to 4, respectively. CI in patients with F3 varices (groups 2 and 4) were significantly higher than those in patients with F2 varices (groups 1 and 3) (p<0.01). The systemic vascular resistances (SVRI) were 2140 +/- 623, 1463 +/- 473, 1916 +/- 420 and 1504 +/- 250 in groups 1 to 4, respectively. SVRI in patients with F3 varices were significantly lower than those in patients with F2 varices (p<0.01). Plasma ammonia levels (NH3) were 78 +/- 27, 162 +/- 153, 80 +/- 27 and 138 +/- 71 in groups 1 to 4, respectively. NH3 in patients with F3 varices were significantly higher than those in patients with F2 varices (p<0.01). The arterio-venous oxygen content differences (Ca-vO2) were 2.93 +/- 0.60, 2.53 +/- 0.55, 2.67 +/- 0.54 and 2.32 +/- 0.64 in groups 1 to 4, respectively. CONCLUSIONS: We conclude that the development of esophagogastric varices is accompanied by deteriorated liver function, hyperdynamic status, increased NH3 and narrowed Ca-vO2.

Hemodynamic effects of combined therapy using partial splenic embolization and transjugular retrograde obliteration for gastric varices with gastrorenal shunt.

BACKGROUND: The purpose of the present study was to investigate the short-term effects of combined therapy using partial splenic embolization (PSE) and transjugular retrograde obliteration (TJO) on the portal hemodynamics of gastric varices with a gastrorenal shunt. PATIENTS AND METHODS: Sixteen patients with gastric varices and a gastrorenal shunt were included in this study. Partial splenic embolization was applied 2 weeks before TJO. The portal blood flow was measured by an ultrasonic duplex Doppler system, and the wedged hepatic venous pressure (WHVP) was measured by hepatic venous catheterization, before and after the combined therapy. RESULTS: The complete obliteration of the gastrorenal shunt and gastric varices was revealed by retrograde shuntography and computed tomography after TJO in all cases. The WHVP before and just after PSE was 23 +/- 7 and 19 +/- 7 mmHg, respectively, showing a significant change (P < 0.01). The WHVP before and the day after TJO was 20 +/- 5 mmHg and 22 +/- 6 mmHg, respectively, showing a significant change (P < 0.01). There was no significant difference between the WHVP before and after the combined therapy. The portal venous flow volume before and after the combined therapy were 514 +/- 146 and 512 +/- 161 ml/min, respectively, showing no significant change. However, the splenic venous flow volume before and after the combined therapy was 319 +/- 131 and 179 +/- 113 ml/min, respectively, showing a significant change (P < 0.05). CONCLUSIONS: The WHVP did not change after the combined therapy of PSE and TJO. Partial splenic embolization contributed to protecting portal congestion after TJO. We conclude that the combined therapy using PSE and TJO is an effective treatment for gastric varices from the portal hemodynamic point of view.

Gastric varices with gastrorenal shunt: combined therapy using transjugular retrograde obliteration and partial splenic embolization.

OBJECTIVE: This study was prospectively conducted to evaluate the effectiveness of the combination of transjugular retrograde obliteration and partial splenic embolization in the treatment of gastric varices with gastrorenal shunt. SUBJECTS AND METHODS: Between November 2002 and December 2006, 14 patients with gastric varices and gastrorenal shunt were treated by combining transjugular retrograde obliteration and partial splenic embolization (group 1). These patients were compared with 19 patients with gastric varices and gastrorenal shunt treated by only transjugular retrograde obliteration (group 2) for the disappearance rate of gastric varices, the cumulative survival rate, and the occurrence rate of esophageal varices after transjugular retrograde obliteration. Partial splenic embolization was performed 7-14 days before transjugular retrograde obliteration. No significant differences were seen between the two groups in terms of demographic data, including age, sex, and Child-Pugh classification. RESULTS: The disappearance rate of gastric varices after transjugular retrograde obliteration was 100% in both groups. The 3-year cumulative survival rate after transjugular retrograde obliteration was 92% in group 1 and 95% in group 2. The 3-year cumulative occurrence rate of esophageal varices after transjugular retrograde obliteration was 9% in group 1 and 45% in group 2, a significant difference (p < 0.05). CONCLUSION: The findings of this study indicate that partial splenic embolization contributed to preventing portal congestion after transjugular retrograde obliteration. We conclude that the combination of transjugular retrograde obliteration and partial splenic embolization for gastric varices is more effective than transjugular retrograde obliteration only in the long-term prevention of esophageal varices after transjugular retrograde obliteration.

Short-term portal hemodynamic effects of partial splenic embolization for hypersplenism.

BACKGROUND/AIMS: The purpose of this study was to investigate the short-term effects of partial splenic embolization (PSE) for hypersplenism on portal hemodynamics and liver function. METHODOLOGY: Thirty-seven patients with hypersplenism were included in this study. RESULTS: The wedged hepatic venous pressure before and after PSE were 39 +/- 10 and 33 +/- 8 cmH2O, respectively, showing significant change (p < 0.01). The flow volumes of the splenic vein before and after PSE were 477 +/- 200 and 319 +/-187 mL/min, respectively, also showing significant change (p < 0.05). However, the flow volumes of the portal vein before and after PSE were 713 +/- 284 and 684 +/- 152 mL/min, respectively, showing no significant change. The blood laboratory parameters showed no significant change after PSE. PSE damaged neither the portal blood flow volume nor the liver function, although it improved the local hyperdynamic state in the splenic area and thrombocytopenia. CONCLUSIONS: In conclusion, PSE is a safe and effective treatment for hypersplenism from the portal hemodynamic point of view.

Combination treatment of partial splenic embolization, endoscopic embolization and transjugular retrograde obliteration for complicated gastroesophageal varices.

The treatment of complicated gastroesophageal varices with a gastrorenal shunt and portal hypertensive gastropathy has not yet been established. We were able to control a case of complicated large gastroesophageal varices with gastrorenal shunt and portal hypertensive gastropathy using a combination treatment of partial splenic embolization, endoscopic embolization and transjugular retrograde obliteration. We first applied partial splenic embolization to reduce the hyperdynamic cycle of portal hypertension and to treat thrombocytopenia. We secondarily applied endoscopic embolization for the esophageal varices. Transjugular retrograde obliteration was performed for the gastric varices 14 days after endoscopic embolization. The wedged hepatic venous pressure had not changed after transjugular retrograde obliteration. After the combination treatment, the gastroesophageal varices were successfully obliterated, but portal hypertensive gastropathy did not worsen. The platelets count, arterial ketone body ratio and ICGR15 were improved. Partial splenic embolization was useful to protect side effects of endoscopic embolization and transjugular retrograde obliteration. We conclude that the combination treatment of partial splenic embolization, endoscopic embolization and transjugular retrograde obliteration is a rational, effective and safe treatment for complicated gastroesophageal varices with gastrorenal shunt and portal hypertensive gastropathy.