Predictors of negative symptoms in the chronic phase of schizophrenia: A cross-sectional study.

This study was designed to investigate the relationship between negative symptoms and key indicators for long-term hospital stays among inpatients with schizophrenia. A further aim was to elucidate the clinical determinants of negative symptoms. The following were used as index factors: age, duration of illness, duration of hospitalization, age at onset, years of education, smoking status, body mass index, concentrations of serum triglycerides, total cholesterol, uric acid, QTc interval duration from electrocardiography, dose equivalents of antipsychotic and anticholinergic agents, neurocognitive function, drug-induced extrapyramidal symptoms, involuntary movements, and psychiatric symptoms. Spearman's rank correlation coefficients were calculated and regression analyses were performed to examine associations between these factors and negative symptoms. Positive symptoms correlated positively with negative symptoms as rated on the Brief Psychiatric Rating Scale. Age at onset correlated negatively with negative symptoms. Multiple regression analysis showed that dose equivalents of atypical antipsychotics and positive symptoms predicted negative symptoms. Increasing our understanding of these predictors as key indicators of the severity of negative symptoms may aid in the reconsideration of therapeutic programs for chronic schizophrenia.

Patients with major depressive disorder exhibit reduced reward size coding in the striatum.

BACKGROUND: Anhedonia is a core symptom of major depressive disorder (MDD). While recent evidence suggests that reduced motivation for reward may be a core feature of anhedonia, the abnormalities in modulatory neural responses to variable reward amounts in MDD patients remain unclear. We investigated whether MDD patients' ability to represent variable-sized monetary rewards in the striatum is disrupted. METHODS: Twelve MDD patients and 12 healthy volunteers completed an assessment of psychometric status and participated in a functional magnetic resonance imaging (fMRI) task that involved the anticipation of financial reward (monetary incentive delay task). The size of the monetary reward was varied among trial conditions and was cued with geometric stimuli. Patients participated in additional fMRI sessions after a 6-week pharmacological treatment with escitalopram, an SSRI. RESULTS: In healthy volunteers, striatal activity increased in proportion to the size of the monetary reward during reward anticipation. This pattern was altered in MDD patients, and significant group-by-reward size interaction effects were observed in the bilateral putamen and the left ventral striatum. Reward sensitivity in motor response and striatum activity at three regions were correlated in healthy controls. In MDD patients, this neurobehavioral coupling was not observed. In addition, changes in the neural reward sensitivity parameter at the left ventral striatum in response to treatment were positively correlated with a reduction of depressive symptoms. CONCLUSIONS: Patients with MDD exhibit reduced ability to modulate neural response when adjusting for variable amount of reward. This result suggests that reward size coding in the striatum may represent a neural correlate of motivational anhedonia in MDD patients.

Increased amygdala reactivity following early life stress: a potential resilience enhancer role.

BACKGROUND: Amygdala hyper-reactivity is sometimes assumed to be a vulnerability factor that predates depression; however, in healthy people, who experience early life stress but do not become depressed, it may represent a resilience mechanism. We aimed to test these hypothesis examining whether increased amygdala activity in association with a history of early life stress (ELS) was negatively or positively associated with depressive symptoms and impact of negative life event stress in never-depressed adults. METHODS: Twenty-four healthy participants completed an individually tailored negative mood induction task during functional magnetic resonance imaging (fMRI) assessment along with evaluation of ELS. RESULTS: Mood change and amygdala reactivity were increased in never-depressed participants who reported ELS compared to participants who reported no ELS. Yet, increased amygdala reactivity lowered effects of ELS on depressive symptoms and negative life events stress. Amygdala reactivity also had positive functional connectivity with the bilateral DLPFC, motor cortex and striatum in people with ELS during sad memory recall. CONCLUSIONS: Increased amygdala activity in those with ELS was associated with decreased symptoms and increased neural features, consistent with emotion regulation, suggesting that preservation of robust amygdala reactions may reflect a stress buffering or resilience enhancing factor against depression and negative stressful events.

Changes in the regional cerebral blood flow detected by arterial spin labeling after 6-week escitalopram treatment for major depressive disorder.

BACKGROUND: A few studies have used pseudo-continuous arterial spin labeling (pCASL) to assess the regional cerebral blood flow (rCBF) in patients with major depressive disorder (MDD). However, rCBF changes during treatment with escitalopram have not been studied in detail. We used pCASL to investigate the effect of 6-week escitalopram treatment on the rCBF in MDD patients. METHODS: We subjected 53 MDD patients and 36 controls to pCASL (T1, baseline). The patients then received treatment with escitalopram for 6 weeks and 27 were scanned again (T2). We used selected regions of interest that exhibited differences between the controls and patients at T1 and compared the T2 rCBF in the patients with the T1 rCBF of the controls. We also compared the T1 and T2 rCBF in the patients to assess their response to escitalopram. RESULTS: After 6-week treatment with escitalopram, the rCBF in the patients' left inferior temporal gyri, the middle- and inferior frontal gyri, and the subgenual anterior cingulate, which had been higher at T1 than in the controls, was decreased. Their rCBF in the right lingual gyrus remained significantly lower at T2. LIMITATION: We did not have a placebo-control group and the number of patients available at T2 was small. CONCLUSION: In MDD patients, 6-week escitalopram treatment elicited significant rCBF changes toward normalization in most of the areas that had shown significant differences between the patients and the controls at T1. The persistence of rCBF anomalies in the right lingual gyrus may be a trait marker of MDD.

Disrupted Brain Activation and Deactivation Pattern during Semantic Verbal Fluency Task in Patients with Major Depression.

BACKGROUND: Patients with major depressive disorder (MDD) exhibit cognitive impairment, and evidence suggests that the semantic version of the verbal fluency task is a reliable cognitive marker of the disorder. Here, using functional magnetic resonance imaging (fMRI), we investigated the dysfunction of neural processing in acute depression and examined the effects of a 6-week pharmacological intervention. METHODS: Sixteen patients with MDD participated in 2 fMRI sessions, and 16 healthy control (HC) subjects participated in 1 fMRI session. During each fMRI session, the participants performed a semantic verbal fluency task. Brain activity during the task was compared between groups (MDD 1st fMRI vs. HC) and times (MDD 1st fMRI vs. 2nd fMRI). RESULTS: Significant brain hypoactivation was observed in MDD patients at the prefrontal, lateral parietal, and limbic regions compared to HC, and MDD patients exhibited hyperactivation at the left precuneus compared to HC. Hypoactivity of the left dorsolateral prefrontal cortex (DLPFC) and hyperactivity of the precuneus were normalized with treatment. CONCLUSIONS: Hypoactivation of the left DLPFC and hyperactivation of the precuneus should be considered as dysregulation of anticorrelated brain networks during a cognitive demanding task. This failure of network regulation may be an important factor in the pathophysiology of MDD.

Direct and indirect influences of childhood abuse on depression symptoms in patients with major depressive disorder.

BACKGROUND: It is known that the onset, progression, and prognosis of major depressive disorder are affected by interactions between a number of factors. This study investigated how childhood abuse, personality, and stress of life events were associated with symptoms of depression in depressed people. METHODS: Patients with major depressive disorder (N = 113, 58 women and 55 men) completed the Beck Depression Inventory-II (BDI-II), the Neuroticism Extroversion Openness Five Factor Inventory (NEO-FFI), the Child Abuse and Trauma Scale (CATS), and the Life Experiences Survey (LES), which are self-report scales. Results were analyzed with correlation analysis and structural equation modeling (SEM), by using SPSS AMOS 21.0. RESULTS: Childhood abuse directly predicted the severity of depression and indirectly predicted the severity of depression through the mediation of personality. Negative life change score of the LES was affected by childhood abuse, however it did not predict the severity of depression. CONCLUSIONS: This study is the first to report a relationship between childhood abuse, personality, adulthood life stresses and the severity of depression in depressed patients. Childhood abuse directly and indirectly predicted the severity of depression. These results suggest the need for clinicians to be receptive to the possibility of childhood abuse in patients suffering from depression. SEM is a procedure used for hypothesis modeling and not for causal modeling. Therefore, the possibility of developing more appropriate models that include other variables cannot be excluded.

Toward Probabilistic Diagnosis and Understanding of Depression Based on Functional MRI Data Analysis with Logistic Group LASSO.

Diagnosis of psychiatric disorders based on brain imaging data is highly desirable in clinical applications. However, a common problem in applying machine learning algorithms is that the number of imaging data dimensions often greatly exceeds the number of available training samples. Furthermore, interpretability of the learned classifier with respect to brain function and anatomy is an important, but non-trivial issue. We propose the use of logistic regression with a least absolute shrinkage and selection operator (LASSO) to capture the most critical input features. In particular, we consider application of group LASSO to select brain areas relevant to diagnosis. An additional advantage of LASSO is its probabilistic output, which allows evaluation of diagnosis certainty. To verify our approach, we obtained semantic and phonological verbal fluency fMRI data from 31 depression patients and 31 control subjects, and compared the performances of group LASSO (gLASSO), and sparse group LASSO (sgLASSO) to those of standard LASSO (sLASSO), Support Vector Machine (SVM), and Random Forest. Over 90% classification accuracy was achieved with gLASSO, sgLASSO, as well as SVM; however, in contrast to SVM, LASSO approaches allow for identification of the most discriminative weights and estimation of prediction reliability. Semantic task data revealed contributions to the classification from left precuneus, left precentral gyrus, left inferior frontal cortex (pars triangularis), and left cerebellum (c rus1). Weights for the phonological task indicated contributions from left inferior frontal operculum, left post central gyrus, left insula, left middle frontal cortex, bilateral middle temporal cortices, bilateral precuneus, left inferior frontal cortex (pars triangularis), and left precentral gyrus. The distribution of normalized odds ratios further showed, that predictions with absolute odds ratios higher than 0.2 could be regarded as certain.

A case of chronic anorexia nervosa with child-bearing by in vitro fertilization necessitating comprehensive team support.

Generalists should be aware of the issues surrounding pregnancy in patients with anorexia nervosa and discuss well with patients and their families before in vitro fertilization.

Psychosocial functioning is correlated with activation in the anterior cingulate cortex and left lateral prefrontal cortex during a verbal fluency task in euthymic bipolar disorder: a preliminary fMRI study.

AIM: Cognitive impairment may account for functional and occupational disability in patients with bipolar disorder even during periods of euthymia. While imaging suggests structural, neurochemical, and functional abnormalities in bipolar disorder patients, the pathophysiology of these deficits has not been elucidated. It was hypothesized that euthymic bipolar patients would have different cortical activation during a verbal fluency task compared to healthy controls, and that psychosocial functioning would be associated with prefrontal cortical activation during the task in the bipolar group. METHODS: Ten euthymic bipolar patients and 10 healthy control participants (matched for age, gender, and years of education) underwent functional magnetic resonance imaging (fMRI) during a verbal fluency task, tapping task and visual task. Correlational analysis between the fMRI brain activation and clinical variables of the participants, including Global Assessment of Functioning (GAF) score, was performed. RESULTS: Compared to the controls, euthymic bipolar patients had significantly greater activation in the bilateral precuneus with similar behavioral performance during the verbal fluency task. There were no significant differences between the groups for the visual task or the simple motor task. Activation in both the left anterior cingulate cortex (ACC) and the left dorsolateral prefrontal cortex (PFC) were significantly positively correlated with GAF score in the euthymic bipolar patients. CONCLUSION: Both the ACC and lateral PFC regions are components of a neural network that plays a critical role in psychosocial functioning, and are often found to be affected in bipolar patients.

Visual imagery while reading concrete and abstract Japanese kanji words: an fMRI study.

Neuroimaging studies have investigated differences in neural correlates between abstract and concrete concepts but this has not been done with Japanese participants. Concrete words have higher imageability than abstract words, such that they elicit more visual imagery. The present study used functional MRI to investigate brain activity of Japanese participants (N=16) during generation of visual images for written concrete or abstract Japanese kanji words. Concrete words elicited significantly more activation than abstract words in the left middle frontal gyrus (LMFG), bilateral superior frontal gyrus, and left fusiform gyrus (LFG). Psychophysiological interaction (PPI) analyses were performed to assess LMFG and LFG functional connections. LMFG activity was accompanied by increased functional interaction with the left superior parietal lobule (LSPL), and LFG activity was accompanied by increased functional interaction with the LMFG. This finding suggests that the LMFG plays an important role in visual imagery, with interactions between this region and both the LSPL and LFG.

Hippocampal activation during associative encoding of word pairs and its relation to symptomatic improvement in depression: a functional and volumetric MRI study.

BACKGROUND: Altered emotional memory is one of the core cognitive functions that causes and maintains depression. Although many studies have investigated the relationship between hippocampal volume, depression and treatment response, no studies have investigated the relationship for hippocampal activity. Additionally, few studies have examined the relationship between functional and structural abnormalities in depression. METHODS: We conducted a functional and volumetric MRI study investigating associative encoding of positive, negative and neutral word pairs in 13 healthy controls, and 14 untreated depressives. We carried out fMRI during a memory-encoding task at baseline. Treatment response was clinically assessed six weeks after pharmacotherapy began. Then, we explored the relation between brain activation during encoding of each word pair and symptomatic improvement. RESULTS: Relative to controls, depressives exhibited decreased activity in the left hippocampus during encoding positive word pairs and, in contrast, increased activity in the right hippocampus during encoding negative or neutral word pairs. Poor response to treatment was associated with smaller activation within the left hippocampus during the memory encoding of positive word pairs. Overall results were not confounded by hippocampal volume. LIMITATIONS: We could not appreciate any disease alteration during the retrieving phase. CONCLUSION: We found qualitative differences in hippocampus functioning between depressives and healthy controls. In addition, the left hippocampus could have an effect on treatment response in depression by contributing to the dysfunctional encoding of positive information.

Distinctive neural responses to pain stimuli during induced sadness in patients with somatoform pain disorder: An fMRI study.

Pain is a multidimensional phenomenon. Patients with somatoform pain disorder suffer from long-lasting pain, with the pathology being closely associated with cognitive-emotional components. Differences between these patients and controls in cerebral responses to pain stimuli have been reported. However, to our knowledge, no studies of somatoform pain disorder have evaluated altered pain-related brain activation as modulated by emotional dysregulation. We examined the distinct neural mechanism that is engaged in response to two different pain intensities in a sad emotional condition, performing functional magnetic resonance imaging (fMRI) on a group of 11 somatoform pain patients and an age-matched control group. Our results showed that the ratio for low-pain intensity ratings between the sad and neutral conditions in patients was higher than in controls. They also showed significant increased activation in the anterior/posterior insula in the low pain sadness condition. Furthermore, there was specific functional connectivity between the anterior insula and the parahippocampus in patients during presentation of low-pain stimuli in the sad context. These findings suggest that a negative emotional context such as sadness contributes to dysfunctional pain processing in somatoform pain disorder. Greater sensitivity to low levels of pain in an emotional context of sadness might be an important aspect of the psychopathology of somatoform pain disorder.

Automatic and intentional brain responses during evaluation of face approachability: correlations with trait anxiety.

BACKGROUND: The judgment of the approachability of others based on their facial appearance often precedes social interaction. Whether we ultimately approach or avoid others may depend on such judgments. METHOD: We used functional magnetic resonance imaging to determine the neural basis for such approachability judgments and the relationship between these judgments and trait anxiety. Participants viewed ambiguous (i.e. neutral) or relatively unambiguous (i.e. angry, happy) faces, assessing either the approachability or the sex of the person depicted. RESULTS: Neutral faces elicited more inconsistent responses within participants only during approachability judgment, suggesting ambiguous property as signals. The contrast pertaining to the interaction between task and face valence demonstrated activation in several areas, such that the left amygdala and medial, middle and inferior frontal gyri were responsive to angry faces when subjects were asked to recognize the sex (implicit task) and to neutral faces when required to discern the approachability (explicit task). Moreover, the blood oxygenation level-dependent change within the left amygdala in response to neutral faces during the judgment of approachability was positively correlated with participant trait anxiety. CONCLUSIONS: These findings extend a proposed model of social cognition by highlighting the functional engagement of the amygdala in approachability judgments, which underlie an individual's sensitivity to ambiguous sources of probable threat.

Sadness enhances the experience of pain and affects pain-evoked cortical activities: an MEG study.

UNLABELLED: Pain is a multidimensional phenomenon. Previous psychological studies have shown that a person's subjective pain threshold can change when certain emotions are recognized. We examined this association with magnetoencephalography. Magnetic field strength was recorded with a 306-channel neuromagnetometer while 19 healthy subjects (7 female, 12 male; age range = 20-30 years) experienced pain stimuli in different emotional contexts induced by the presentation of sad, happy, or neutral facial stimuli. Subjects also rated their subjective pain intensity. We hypothesized that pain stimuli were affected by sadness induced by facial recognition. We found: 1) the intensity of subjective pain ratings increased in the sad emotional context compared to the happy and the neutral contexts, and 2) event-related desynchronization of lower beta bands in the right hemisphere after pain stimuli was larger in the sad emotional condition than in the happy emotional condition. Previous studies have shown that event-related desynchronization in these bands could be consistently observed over the primary somatosensory cortex. These findings suggest that sadness can modulate neural responses to pain stimuli, and that brain processing of pain stimuli had already been affected, at the level of the primary somatosensory cortex, which is critical for sensory processing of pain. PERSPECTIVE: We found that subjective pain ratings and cortical beta rhythms after pain stimuli are influenced by the sad emotional context. These results may contribute to understanding the broader relationship between pain and negative emotion.

The effect of negative and positive emotionality on associative memory: an FMRI study.

In general, emotion is known to enhance memory processes. However, the effect of emotion on associative memory and the underling neural mechanisms remains largely unexplored. In this study, we explored brain activation during an associative memory task that involved the encoding and retrieval of word and face pairs. The word and face pairs consisted of either negative or positive words with neutral faces. Significant hippocampal activation was observed during both encoding and retrieval, regardless of whether the word was negative or positive. Negative and positive emotionality differentially affected the hemodynamic responses to encoding and retrieval in the amygdala, with increased responses during encoding negative word and face pairs. Furthermore, activation of the amygdala during encoding of negative word and neutral face pairs was inversely correlated with subsequent memory retrieval. These findings suggest that activation of the amygdala induced by negative emotion during encoding may disrupt associative memory performance.

[Cognition, behavior and emotion in psychotherapy--an example of cognitive behavioral therapy for depression].

The development of neuroimaging methods has enabled significant advances toward elucidating the mechanism of cognition, behavior and emotion. This article first reviews recent human neuroimaging studies that examined the neurocircuitry of emotion and emotion regulation. Next, we review the neuroimaging literature of the effects of cognitive behavioral therapy for depression. Lastly, we provide the brain mechanism that the emotional support regulates psychological pain in ostracism, and then discuss a biological model of psychotherapy. We hope that the present review can help us, not only to better understand the biological basis of cognition, behavior and emotion in psychotherapy, but also to be aware of effects of psychotherapy on brain.

Anterior cingulate cortex modulates preparatory activation during certain anticipation of negative picture.

We studied the neural activation associated with anticipations of emotional pictures using functional magnetic resonance imaging (fMRI) by directly comparing certain with uncertain anticipation conditions. While being scanned with fMRI, healthy participants (n=18) were cued to anticipate and then perceive emotional stimuli having predictable (i.e., certain) emotional valences (i.e., positive and negative), given a preceding cue, as well as cued stimuli of uncertain valence (positive or negative). During anticipation of pictures with certain negative valence, activities of supracallosal anterior cingulate cortex, ventrolateral prefrontal cortex, insula, and amygdala were enhanced relative activity levels that for the uncertain emotional anticipation condition. This result suggests that these brain regions are involved in anticipation of negative images, and that their activity levels may be enhanced by the certainty of anticipation. Furthermore, the supracallosal anterior cingulate cortex showed functional connectivity with the insula, prefrontal cortex, and occipital cortex during the certain negative anticipation. These findings are consistent with an interpretation that top-down modulation, arising from anterior brain regions, is engaged in certain negative anticipation within the occipital cortex. It is thought that the limbic system involving the amygdala, ACC, and insula, engaged emotional processes, and that the input system involving the visual cortex entered an idling state.

Importance of early lighting conditions in maternal care by dam as well as anxiety and memory later in life of offspring.

Rodent studies have revealed that the early rearing environment plays an important role in the development of stress vulnerability, memory and cognition. Although early lighting conditions (ELC) are involved in these neuronal developments through both maternal and offspring behavior, their influence has not been fully elucidated. Thus, by using Sprague-Dawley rats, we examined whether ELC affected maternal care by the dam and the subsequent neurodevelopment of the offspring. Prolonged dark phase conditions (PDC) (light/dark, 6/18 h) and prolonged light phase conditions (light/dark, 18/6 h) were administered from postnatal day 2 to postnatal day 14. Throughout this period, maternal care and the circadian rhythmicity of dams were investigated. In adolescence and adulthood of the offspring, we measured anxiety-like behavior, social interaction, object recognition memory, activity rhythm and corticosterone response to stress with hippocampal expression of N-methyl-D-aspartate and glucocorticoid receptor mRNAs. PDC altered maternal care and circadian rhythmicity in the dam compared with normal lighting conditions and prolonged light phase conditions. PDC markedly increased anxiety-like behavior, decreased social interaction and object recognition memory, and inhibited corticosterone feedback in offspring later in life. Furthermore, hippocampal levels of glucocorticoid receptor mRNA and N-methyl-D-aspartate receptor 2B mRNA in rats subjected to PDC were significantly lower than in animals subjected to normal lighting conditions. In the adult offspring, the circadian rhythm of locomotor activity was not affected. These findings suggested that ELC affect mother-infant interactions and subsequently at least partially alter the neurobehavioral development of offspring.

Importance of early environment in the development of post-traumatic stress disorder-like behaviors.

A number of clinical studies in which early adversities were defined retrospectively, demonstrated that early adverse experiences increased the morbidity rate of post-traumatic stress disorder (PTSD) in later life. However, no prospective studies have yet been conducted to elucidate whether early adversity affects the risk or severity of PTSD. Thus, we examined whether early adversity would strengthen the severity of PTSD symptoms in later life by using neonatal isolation (NI) and single prolonged stress (SPS) as an animal model of PTSD. We measured anxiety-like behavior in the elevated plus maze (EPM), contextual freezing in the contextual fear (CF) test, and analgesia in the flinch-jump and hot-plate tests in four groups of adult rats (sham, NI, SPS, and NI+SPS). NI significantly enhanced the SPS-induced decrease in the percentage of open arm time and open arm entries in the EPM, enhanced the SPS-induced increase in contextual freezing, and strengthened SPS-induced analgesia, without any changes in locomotor activity in the open field locomotor test. In addition, we examined the effect of environmental enrichment (EE). Repeated exposure to EE ameliorated the NI-induced enhancement of contextual freezing, but not anxiety-like behavior or analgesia, in response to SPS. The results of the present study demonstrated that while early adversity strengthened PTSD-like symptoms, EE alleviated the enhanced contextual freezing by NI and SPS. These findings suggest that early adversity may worsen dysfunction of the amygdala and hippocampus in PTSD, and an early intervention may alleviate the early adversity-mediated enhancement of hippocampal dysfunction in PTSD.