Shigeru Toki

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.

Neonatal tactile stimulation reverses the effect of neonatal isolation on open-field and anxiety-like behavior, and pain sensitivity in male and female adult Sprague–Dawley rats

It is well known that early life events induce long-lasting psychophysiological and psychobiological influences in later life. In rodent studies, environmental enrichment after weaning prevents the adulthood behavioral and emotional disturbances in response to early adversities. We compared the behavioral effect of neonatal isolation (NI) with the effect of NI accompanied by tactile stimulation (NTS) to determine whether NTS could reverse or prevent the effects of NI on the adulthood behavioral and emotional responses to environmental stimuli. In addition, we also examined the sex difference of the NTS effect. Measurements of body weights, an open-field locomotor test, an elevated plus maze test, a hot-plate test, and a contextual fear-conditioning test were performed on postnatal day 60. As compared with rats subjected to NI, rats subjected to NTS showed significantly higher activity and exploration in the open-field locomotor test, lower anxiety-like behavior in the elevated plus maze test, and significantly prolonged latencies in the hot-plate test, and this effect was equal among males and females. In the contextual fear-conditioning test, whereas NTS significantly reduced the enhanced freezing time due to NI in females, no significant difference in the freezing time between NI and NTS was found in males. These findings indicate that adequate tactile stimulation in early life plays an important role in the prevention of disturbances in the behavioral and emotional responses to environmental stimuli in adulthood induced by early adverse experiences.

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.

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.

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 persons 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.

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.

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.

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

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.

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.

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

BackgroundIt 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.MethodsPatients 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.ResultsChildhood 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.ConclusionsThis 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.