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Psychiatry research has long experienced a stagnation stemming from a lack of understanding of the neurobiological underpinnings of phenomenologically defined mental disorders. Recently, the application of computational neuroscience to psychiatry research has shown great promise in establishing a link between phenomenological and pathophysiological aspects of mental disorders, thereby recasting current nosology in more biologically meaningful dimensions. In this review, we highlight recent investigations into computational neuroscience that have undertaken either theory- or data-driven approaches to quantitatively delineate the mechanisms of mental disorders. The theory-driven approach, including reinforcement learning models, plays an integrative role in this process by enabling correspondence between behavior and disorder-specific alterations at multiple levels of brain organization, ranging from molecules to cells to circuits. Previous studies have explicated a plethora of defining symptoms of mental disorders, including anhedonia, inattention, and poor executive function. The data-driven approach, on the other hand, is an emerging field in computational neuroscience seeking to identify disorder-specific features among high-dimensional big data. Remarkably, various machine-learning techniques have been applied to neuroimaging data, and the extracted disorder-specific features have been used for automatic case-control classification. For many disorders, the reported accuracies have reached 90% or more. However, we note that rigorous tests on independent cohorts are critically required to translate this research into clinical applications. Finally, we discuss the utility of the disorder-specific features found by the data-driven approach to psychiatric therapies, including neurofeedback. Such developments will allow simultaneous diagnosis and treatment of mental disorders using neuroimaging, thereby establishing 'theranostics' for the first time in clinical psychiatry. [ABSTRACT FROM AUTHOR]

The human brain is characterized by an evolutionarily new, highly developed neocortex, which has characteristic connections with phylogenically older structures to enable adaptation to complex social environments. Adaptive social behavior requires successful mental representations of the self and others’ emotions and intentions. Measurement of brain activity under laboratory-based settings has been the gold standard in previous cognitive neuroscience studies. However, these measurement settings may be sub-optimal if we want to visualize brain function in active individuals in real-world environments. Neuroscience has historically developed through generations of the “sensing brain,” “emotional brain,” “social brain,” and “ego brain.” The next generation is the “action brain” combined with “real-world neuroscience” perspective. To enable in situ measurement of the action brain, real-world or two-person neuroimaging techniques are necessary to visualize brain dynamics during natural social situations, such as the presence of others. This review discusses recent literature describing non-human primate (NHP) and human brain functions during active behaviors in social environments. Uncovering the neurobiological mechanisms of the active brain in the presence of others by using real-world neuroimaging will be an important step toward fully understanding the human brain and its mental functions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Depression is a major risk factor for suicide, but few studies have examined psychosocial risk factors for suicide in clinical patients with depression. The purpose of this study was to investigate psychosocial factors which could be associated with suicidal ideation in clinical patients with depression including: sick-leave, help-seeking behavior, and reluctance to admit mental health problems. Methods: A multi-center cross-sectional survey using self-report questionnaire was conducted at 54 outpatient psychiatric clinics in Tokyo in 2012. Adult outpatients who were diagnosed by psychiatrists as mood disorders (F30–F39) in the International Classification of Diseases-10 (ICD-10) were included in the study. Those who met the criteria for current hypomanic or manic episode were excluded from the study. Results: A total of 189 patients with depression participated in the survey. Multivariable logistic regression analysis showed that taking sick-leave and having sought help from family were associated with decreased odds of current suicidal ideation. Moderate or more severe depression was associated with increased odds of suicidal ideation, and reluctance to admit own mental health problem tended to increase odds of suicidal ideation. Limitations: Living status and suicidal ideation before consultation with psychiatrist were not investigated. Severity of suicidal ideation and comorbid psychiatric disorders were not assessed. Conclusions: Importance of treatment of more severe depression for suicide prevention was confirmed. Industrial health staffs should consider the possibility of positive effect of taking sick-leave when they see employees with depression. Promoting help-seeking for family and reducing stigma of mental illness may be effective for suicide prevention. [Copyright &y& Elsevier]

Abstract: Unlike other primates, humans can regulate their own minds and brains and establish the self, which are based on language acquisition and social reciprocity. This capacity for self-regulation is evolutionarily realized by the highly developed neocortex and developmentally matures during adolescence. Inappropriate maturation of the neural systems responsible for self-regulation in adolescence could lead to the emergence of psychiatric disorders, such as schizophrenia. Schizophrenia is a devastating psychiatric disorder, the onset of which usually takes place during adolescence/youth; one of its core features is disturbance of self-related information processing. Although schizophrenia has been associated with neurodevelopmental abnormalities during the perinatal period, recently improved neuroimaging techniques have shown progressive deterioration in the structure and function of neocortical regions in the prodromal and first-episode stages of the disorder. These reconsiderations have stimulated neurobiological investigations into the normal developmental process and its disturbance of the glutamatergic/synaptic system in adolescence. Of late, clinical psychiatry has been seeking early intervention strategies by integrating biological and psychosocial approaches. By integrating epidemiology, social neuroscience, and psychiatry, we aim to establish a new interdisciplinary science to uncover the developmental mechanisms of self-regulation in adolescence and create supportive and preventive strategies, which will ultimately contribute to education and society. [Copyright &y& Elsevier]

Abstract: Patients with schizophrenia have low extraversion and high neuroticism. These personality traits affect the everyday life of patients with schizophrenia, making it important to investigate neurobiological basis of personality traits. In healthy people, extraversion is associated with hemodynamic responses in the amygdala and electrophysiological brain activity such as event-related potential and event-related desynchronization during emotional face processing. Patients with schizophrenia show abnormal neural activity during emotional face processing, such as an N170 amplitude reduction. However, few studies to date have reported an association between personality traits and neural activity during emotional face processing in schizophrenia. In the present study, we examined N170 during emotional face processing, and association with personality traits in patients with schizophrenia. Fifteen male patients with chronic schizophrenia and 15 healthy male subjects participated in this study. Patients with schizophrenia had reduced N170 amplitudes (p =0.007). While healthy subjects had increased N170 amplitudes in response to emotional faces compared with neutral faces (p =0.003), patients with schizophrenia showed no difference in N170 amplitudes between emotional and neutral faces (p =0.60). Reduced N170 amplitude in response to neutral faces was correlated with low extraversion scores in patients with schizophrenia (r s =−0.69, p =0.005). The abnormal N170 and its association with extraversion in schizophrenia were found at the right rather than the left posterior temporal electrode. An abnormal N170 in schizophrenia may reflect impairments in the structural encoding of emotional faces, and indiscrimination between emotional and neutral faces at this stage of information processing. The association between abnormal N170 amplitudes and extraversion suggests that abnormal neural activity in the early stages of emotional face processing may underlie low extraversion characteristic of schizophrenia. [Copyright &y& Elsevier]

Background: Controversy exists over the nature and origin of reduced regional brain volumes in posttraumatic stress disorder (PTSD). At issue is whether these reductions represent preexisting vulnerability factors for developing PTSD upon traumatic exposure or acquired PTSD signs due to the traumatic stress that caused the PTSD or the chronic stress of having the disorder (or both). We employed a case–control design in monozygotic twin pairs discordant for combat exposure to address the preexisting versus acquired origin of brain morphometric abnormalities in PTSD. Methods: We used voxel-based morphometry to search for gray matter density reductions in magnetic resonance imaging (MRI) data obtained in a previous study of combat-exposed Vietnam veteran twins with (n = 18) versus without (n = 23) PTSD and their “high-risk” versus “low-risk” (respectively) identical combat-unexposed cotwins. Results: Compared with the combat-exposed twins without PTSD, the combat-exposed twins with PTSD showed significant gray matter density reductions in four predicted brain regions: right hippocampus, pregenual anterior cingulate cortex (ACC), and left and right insulae. There was a significant PTSD Diagnosis × Combat Exposure interaction in pregenual ACC in which combat-exposed PTSD twins had lower gray matter density than their own combat-unexposed cotwins as well as than the combat-exposed twins without PTSD and their cotwins. Conclusions: The results point to gray matter volume diminutions in limbic and paralimbic structures in PTSD. The pattern of results obtained for pregenual ACC suggests that gray matter reduction in this region represents an acquired sign of PTSD consistent with stress-induced loss. [Copyright &y& Elsevier]

Abstract: Functional neuroimaging studies to date have shown prefrontal dysfunction during executive tasks in schizophrenia. However, relationships between hemodynamic response in prefrontal sub-regions and clinical characteristics have been unclear. The objective of this study is to evaluate prefrontal hemodynamic response related to an executive task in schizophrenia and to assess the relationship between activation in the prefrontal sub-regions and clinical status. Fifty-five subjects with schizophrenia and age- and gender-matched 70 healthy subjects were recruited for this case-control study in a medical school affiliated hospital in the Tokyo metropolitan area, Japan. We measured hemoglobin concentration changes in the prefrontal (dorsolateral, ventrolateral, and frontopolar regions) and superior temporal cortical surface area during verbal fluency test using 52-channel near-infrared spectroscopy, which enables real-time monitoring of cerebral blood volumes in the cortical surface area under a more restraint-free environment than positron emission tomography or functional magnetic resonance imaging. The two groups showed distinct spatiotemporal pattern of oxy-hemoglobin concentration change during verbal fluency test. Schizophrenia patients were associated with slower and reduced increase in prefrontal activation than healthy controls. In particular, reduced activations of the frontopolar region, rather than lateral prefrontal or superior temporal regions, showed significant positive correlations with lower global assessment of functioning scores in the patient group, although task performance was not significantly associated with the scores. These results suggest that reduced frontopolar cortical activation is associated with functional impairment in patients with schizophrenia and that near-infrared spectroscopy may be an efficient clinical tool for monitoring these characteristics. [Copyright &y& Elsevier]

It is unclear whether the severity of positive formal thought disorder, a core clinical feature of schizophrenia, is stable or worsening through the chronic course of the illness. The neurocognitive basis for positive thought disorder also remains unclear. The aim of the present paper was to examine the relationship between thought disorder as measured by the Thought Disorder Index (TDI) and duration of illness and neuropsychological indices in 79 patients with schizophrenia. TDI scores increased in proportion to illness duration. TDI scores were not associated with verbal memory or executive functioning. These results indicate an ongoing worsening of positive thought disorder through the course of illness in schizophrenia. [ABSTRACT FROM AUTHOR]

Individuals with pervasive developmental disorder (PDD) are characterized by deficits in socialization. To date, moral judgment, which may have a considerable influence on socialization, has not been fully investigated in high-functioning PDD (HFPDD), particularly from a viewpoint of practical adjustment with peers. Human External Action and its internal Reasoning Type (HEART), a standardized test for evaluating moral judgment in school children developed in Japan, was used to compare various aspects of moral judgment between 23 students with HFPDD (6–14 years old) and 23 students with typical development matched for age, intelligence, and socioeconomic status. Students with HFPDD scored significantly lower on Internal Moral Reasoning than control students. As for the level of Internal Moral Reasoning, while both groups reached a conventional (third) level in almost all items, fewer students with HFPDD achieved an autonomous (fourth) level and more students with HFPDD remained at a heteronomous (second) level than did control students. In the HFPDD group there were significant positive correlations between some items of Internal Moral Reasoning and verbal ability-related items of Wechsler Intelligence Scale for Children-III. A comparatively lower score in students with HFPDD may relate to difficulty in socialization. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We evaluated event-related potentials (ERPs) elicited by attentional disengagement in individuals with autism. Methods: Sixteen adults with autism, 17 adults with mental retardation and 14 healthy adults participated in this study. We recorded the pre-saccade positive ERPs during the gap overlap task under which a peripheral stimulus was presented subsequent to a stimulus in the central visual field. Under the overlap condition, the central stimulus remained during the presentation of the peripheral stimulus and therefore participants need to disengage their attention intentionally in order to execute the saccade to the peripheral stimulus due to the preservation of the central stimulus. Results: The autism group elicited significantly higher pre-saccadic positivity during a period of 100–70ms prior to the saccade onset than the other groups only underthe overlap condition. The higher amplitude of pre-saccadic positivity in the overlap condition was significantly correlated with more severe clinical symptoms within the autism group. Conclusions: These results demonstrate electrophysiological abnormalities of disengagement during visuospatial attention in adults with autism which cannot be attributed to their IQs. Significance: We suggest that adults with autism have deficits in attentional disengagement and the physiological substrates underlying deficits in autism and mental retardation are different. [Copyright &y& Elsevier]

Abstract: Previous studies showing prolongation of auditory P300b latency with increasing age provided support for post-onset progressive change in schizophrenia. We sought to extend the findings by evaluating the effects of gender and the subcomponents (P3b versus P3a) in schizophrenia (N =108) and controls (N =70). P3b latency significantly correlated with age in schizophrenia (Spearman''s rho=0.214, P =0.026) and in male patients with schizophrenia (rho=0.260, P =0.049) whereas, it did not reach significance in female patients with schizophrenia (rho=0.174, P =0.23). P3a latency showed no correlation. Our findings may provide evidence for progressive change in the brain function in schizophrenia, and this change may be slower in female than male patients. P3b may serve as a more sensitive index for cognitive decline than P3a. [Copyright &y& Elsevier]

Abstract: Functional neuroimaging studies have suggested that dysfunction of prefrontal cortex (PFC) is present in persons with pervasive developmental disorders (PDD). Recently, the development of near-infrared spectroscopy (NIRS) has enabled noninvasive bedside measurement of regional cerebral blood volume. Although NIRS enables the noninvasive clarification of brain functions in many psychiatric disorders, it has not yet been used to examine subjects with PDD. The aim of our study was to conduct an NIRS cognitive activation study to verify PFC dysfunction in PDD. The subjects were 10 adults with PDD and 10 age- and gender-matched healthy subjects. Hemoglobin concentration changes were measured with a 24-channel NIRS machine during the letter fluency task. While the number of words generated during the letter fluency task did not differ significantly between groups, the analysis of covariance including IQ as a confounding covariate showed that the PDD group was associated with bilateral reduction in oxy-hemoglobin concentration change as compared with the control group. The statistical results did not change when only IQ-matched high-functioning subjects (N =7) were included. Moreover, reduced oxy-hemoglobin concentration change for the right PFC was significantly correlated with verbal communication deficits within the PDD group. The present findings are consistent with proposed prefrontal dysfunction in PDD subjects identified by other neuroimaging modalities. The present results may be also potentially useful for applying NIRS to clinical settings of child psychiatry. [Copyright &y& Elsevier]

Abstract: The present study was performed to determine the effect of perospirone, a novel antipsychotic drug with D2/5-HT2A antagonist and partial 5-HT1A agonist properties, on auditory P300 in eight patients with chronic schizophrenia. Switching to an equivalent dose of perospirone from prior antipsychotic medication was associated with a significant improvement in the negative symptoms of the positive and negative syndrome scale (PANSS). The change in P300 amplitude following a switch to perospirone correlated significantly with the improvement of general psychopathology symptoms, as well as with the change in scores on items of delusions, hallucinatory behavior, emotional withdrawal, depression, poor attention, and disturbance of volition. These results suggest that clinical improvement in response to perospirone in some patients may, at least in part, be mediated through cognitive change indexed by P300 in chronic schizophrenia. [Copyright &y& Elsevier]

Abstract: The auditory mismatch negativity (MMN) or its magnetic counterpart (magnetic mismatch field, MMF) has been widely used to assess the ability of stimulus-driven change detection process in humans. The authors evaluated the similarity of inter-individual variation of the response strength between MMN and MMF recordings. Three types of MMN or MMF were recorded in ten healthy subjects: change in duration of pure-tone stimuli, change in duration of the Japanese vowel /a/, and difference between the Japanese vowels /a/ and /o/. There was no significant correlation between MMN amplitude and MMF strength under any condition and in either hemisphere. These results suggest that widely used indices of MMN in the two technologies, i.e., EEG-amplitude and MEG–ECD may not be proportional in an individual. To further clarify the differential significance of recording MMN/MMF may be important to establish MMN/MMF as clinical indices of individual ability of preattentive stage of auditory processing. [Copyright &y& Elsevier]

Abstract: Objective: Autism is a form of pervasive developmental disorder in which dysfunction in interpersonal relationships and communication is fundamental. This study evaluated neurophysiological abnormalities at the basic level of language processing, i.e. automatic change detection of speech and non-speech sounds, using magnetoencephalographic recording of mismatch response elicited by change in vowels and tones. Methods: The auditory magnetic mismatch field (MMF) was evaluated in 9 adults with autism and 19 control subjects using whole-head magnetoencephalography. The MMF in response to the duration change of a pure tone or vowel /a/ and that in response to across-phoneme change between vowels /a/ and /o/, were recorded. Results: The groups were not significantly different in MMF power under any conditions. However, the autism group showed a left-biased latency prolongation of the MMF particularly under the across-phoneme change condition, and this latency delay was significantly associated with greater symptom severity. Conclusions: These results suggest that adults with autism are associated with delayed processing for automatic change detection of speech sounds. These electrophysiological abnormalities at the earliest level of information processing may contribute to the basis for language deficits observed in autism. Significance: These results provide the first evidence for delayed latency of phonetic MMF in adults with autism. [Copyright &y& Elsevier]

Abstract: Previous investigations of auditory P300 event-related potentials have provided electrophysiological evidence for attentional problems in patients with posttraumatic stress disorder (PTSD). The present study sought to evaluate the relationship between P300 deficits and underlying brain morphological abnormalities in never-treated, comorbidity-free patients with PTSD following the Tokyo subway sarin attack. Out of 47 victims recruited, 8 victims with PTSD and 13 victims without PTSD were identified. Correlational analyses were performed between auditory P300 amplitude at Pz electrode site elicited in an oddball task and anterior cingulate gray matter volume that was shown to be reduced in our previous study using voxel-based morphometry on magnetic resonance imaging. Victims with PTSD showed significantly lower amplitudes of P300 compared with victims without PTSD, and the lower P300 amplitudes at Pz were significantly associated with higher avoidance/numbing scores in the PTSD group. Furthermore, in the PTSD group only, the P300 amplitudes showed a trend toward significant positive correlation with voxel densities of the anterior cingulate cortex gray matter. These results provide the first evidence that electrophysiological deficits of controlled attention observed in patients with PTSD may be linked to underlying brain morphological abnormalities. [Copyright &y& Elsevier]

Abstract: We applied high resolution event-related potentials (ERPs) to assess brain activities associated with inhibition of irrelevant information processing during auditory selective attention. Ten healthy subjects performed an auditory selective attention task. ERPs in response to standard stimuli delivered to the unattended ear (irrelevant stimuli) and those delivered to the attended ear (relevant stimuli) were evaluated using temporally sequential scalp current density (SCD) mappings. For the irrelevant stimuli, current sources were located in the mid-frontal regions at 140–220ms post-stimuli, and these SCD values were significantly larger than those for the relevant stimuli. These results suggest that auditory selective attention process involves not only focusing attention on relevant information, but also inhibitory processing of irrelevant information mediated by the frontal cortex. [Copyright &y& Elsevier]

A high prevalence of abnormal cavum septi pellucidi (CSP) in schizophrenia may reflect neurodevelopmental abnormalities in midline structures of the brain. The relationship, however, between abnormal CSP and clinical symptoms, and with abnormalities in other limbic structures remains unclear, as does the question of whether a similar abnormality is present in affective psychosis. Seventy-four patients at their first hospitalization, 33 with schizophrenia and 41 with affective (mainly manic) psychosis, and 56 healthy control subjects underwent high-spatial-resolution magnetic resonance imaging (MRI). CSP on six slices or more on 0.9375-mm resampled coronal images was categorized as abnormal. The prevalence of abnormal CSP in both schizophrenic patients (26.1%) and affective psychosis patients (18.2%) was significantly higher than was observed in control subjects (8.2%). In schizophrenic patients only, larger CSP was significantly associated with more severe thinking disturbance and smaller left parahippocampal gyrus gray matter volumes. While the relationships between CSP ratings and clinical symptoms did not significantly differ between the two psychosis groups as assessed by the comparison of regression slopes, the association with limbic volumes appeared to be specific to schizophrenic patients. These results suggest that psychosis associated with schizophrenia and affective disorder share, at least to some extent, neurodevelopmental abnormalities involving midline structures and associated psychopathological consequences. However, the association between abnormal CSP and limbic systems may be more specific to schizophrenia. [ABSTRACT FROM AUTHOR]

This paper reviews recent empirical findings related to prefrontal and executive function in unipolar depression. While a number of reviews have dealt with either the neuropsychological literature or findings from imaging studies, the present review addresses both, as well as findings from studies that have combined brain-imaging techniques with neuropsychological measures. This combined approach is of great interest as the performance of a structured task may act to load the areas of interest and reduce variance, thus making the imaging evidence more valuable; while the use of imaging provides a check that the neuropsychological tasks are indeed engaging the structures whose performance they are intended to assess. Prominent models of the neurobiology of depression implicate involvement of the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). The evidence from combined imaging and neuropsychological studies supports the involvement of the ACC, but is less clear in the case of the DLPFC. However, the limited number of such studies conducted to date means that conclusions must be tentative and further studies employing this combined approach may be of great value. [Copyright &y& Elsevier]

We used the combination of magnetic resonance imaging (MRI), event-related potentials (ERPs), and magnetoencephalography (MEG) to track structural and functional abnormalities of the superior temporal gyrus (STG) and its subdivisions of Heschl''s gyrus (HG; primary auditory cortex) and planum temporale (PT; language-related association cortex) in schizophrenia. We found a significantly progressive decrease of left posterior STG gray matter volume at 1.5-year follow-up in first-episode patients with schizophrenia. When STG was divided into HG and PT, both showed a similar degree of volume reduction over time in patients with schizophrenia. Structural abnormalities of HG at the first-hospitalization and their progression were tightly coupled with the amplitude of mismatch negativity (MMN) elicited by tones, an ERP index of auditory sensory memory with the major generator in HG, in patients with schizophrenia. Moreover, in independent samples of schizophrenia, we showed that patients were associated with pronounced reduction of MMN amplitude elicited by speech sounds and its MEG counterpart (magnetic mismatch field, MMF). Finally, we found a significant correlation between MMF powers elicited by speech sounds and gray matter volumes of PT in patients with schizophrenia but not in control subjects. These converging results suggest a presence of progressive process in the structure and function of the auditory cortex in schizophrenia. [Copyright &y& Elsevier]

Schizophrenia is associated with dysfunction in language processing. At the earliest stage of language processing, dysfunction of categorical perception of speech sounds in schizophrenia has been demonstrated in a behavioral task. The aim of this study was to assess automatic categorical perception of speech sounds as reflected by event-related changes in magnetic field power in schizophrenia. Using a whole-head magnetoencephalographic recording, the magnetic counterpart of mismatch negativity (MMNm) elicited by a phonetic change was evaluated in 16 right-handed patients with chronic schizophrenia and in 19 age-, sex-, and parental socioeconomic status-matched normal control subjects. Three types of MMNm (MMNm in response to a duration decrement of pure-tone stimuli; a vowel within-category change [duration decrement of Japanese vowel /a/]; vowel across-category change [Japanese vowel /a/ versus /o/]) were recorded. While the schizophrenia group showed an overall reduction in magnetic field power of MMNm, a trend was found toward more distinct abnormalities under the condition of vowel across-category change than under that of duration decrement of a vowel or tone. The patient group did not show abnormal asymmetries of MMNm power under any of the conditions. This study provides physiological evidence for impaired categorical perception of speech sounds in the bilateral auditory cortex in schizophrenia. The language-related dysfunction in schizophrenic patients may be present at the early stage of auditory processing of relatively simple stimuli such as phonemes, and not just at stages involving higher order semantic processes. [Copyright &y& Elsevier]

Objective: Smaller temporal lobe cortical gray matter volumes, including the left superior temporal gyrus, have been reported in magnetic resonance imaging (MRI) studies of patients with chronic schizophrenia and, more recently, in patients with first-episode schizophrenia. However, it remains unknown whether there are progressive decreases in temporal lobe cortical gray matter volumes in patients with first-episode schizophrenia and whether similarly progressive volume decreases are present in patients with affective psychosis.Method: High-spatial-resolution MRI scans at initial hospitalization and 1.5 years later were obtained from 13 patients with first-episode schizophrenia, 15 patients with first-episode affective psychosis (mainly manic), and 14 healthy comparison subjects. MRI volumes were calculated for gray matter of superior temporal gyrus and for the amygdala-hippocampal complex.Results: Patients with first-episode schizophrenia showed significant decreases in gray matter volume over time in the left superior temporal gyrus compared with patients with first-episode affective psychosis or healthy comparison subjects. This progressive decrease was more pronounced in the posterior portion of the left superior temporal gyrus (mean=9.6%) than in the anterior portions (mean=8.4%). No group differences in the rate of change over time were present in other regions.Conclusions: These findings demonstrate a progressive volume reduction of the left posterior superior temporal gyrus gray matter in patients with first-episode schizophrenia but not in patients with first-episode affective psychosis. [ABSTRACT FROM AUTHOR]

The continuous performance test (CPT) provides a reliable index of cognitive function, but it is still unclear what aspects of processing this test measures. This study aimed to investigate the contribution of different aspects of cognitive function to the performance on degraded stimulus CPT (DSCPT), which requires a higher level of mental effort than the conventional CPT. Event-related potential (ERP) components, MMN, N2b, and early and late Nds were measured at 16 electrode sites in 19 right-handed normal volunteers using an auditory selective attention task. The association between CPT sensitivity ratings (sensitivity A′) and amplitudes of each component was examined for each electrode site. The CPT sensitivity A′ showed a significant positive correlation with the N2b amplitude in the fronto-central and temporal regions, predominantly in the right hemisphere and specifically to the right ear of stimulation. This finding suggests that the controlled deviance detection process was related to DSCPT performance. [Copyright &y& Elsevier]

Schizophrenia is a major mental disorder, characterized by their set of symptoms, including hallucinatory-delusional symptoms, thought disorder, emotional flattening, and social withdrawal. Since 1980s, advances in neuroimaging and neurophysiological techniques have provided tremendous merits for investigations into schizophrenia as a brain disorder. In this article, we first overviewed neuroanatomical studies using structural magnetic resonance imaging (s-MRI), MR spectroscopy (MRS), and postmortem brains, followed by neurophysiological studies using event-related potentials (ERPs) and magnetoencephalography (MEG), in patients with schizophrenia. Evidences from these studies suggest that schizophrenia is a chronic brain disorder, structurally and functionally affecting various cortical and subcortical regions involved in cognitive, emotional, and motivational aspects of human behavior. Second, we reviewed recent investigations into neurobiological basis for schizophrenic symptoms (auditory hallucinations and thought disorder) using these indices as well as hemodynamic assessments such as positron emission tomography (PET) and functional MRI (f-MRI). Finally, we addressed the issue of the heterogeneity of schizophrenia from the neurobiological perspective, in relation to the neuroanatomical and neurophysiological measures. [Copyright &y& Elsevier]

The auditory mismatch negativity (MMN) of event-related potential components has been widely used to assess the ability of auditory automatic change discrimination of verbal and nonverbal stimuli in healthy individuals and patients with various illnesses. To clarify the role of gender differences in the MMN, we compared the amplitude, latency, and topography of tonal and phonetic MMN between healthy males and females, using a high-density (128 channel) electroencephalography montage. The MMN was evaluated in 18 right-handed male and ten age-matched female adults. The MMN in response to a duration change of pure tone and that in response to a phonetic change (Japanese vowel /a/ versus /o/ with 150-ms duration) were recorded. There were no significant differences in amplitude, latency, or laterality for either tonal or phonetic MMN between male and female subjects. This lack of evidence for effects of gender on MMN in response to duration change of tones or that in response to changes of phonemes with a short duration in normal adults may be of relevance to a growing number of researchers who are studying the MMN in healthy individuals and various clinical groups. [Copyright &y& Elsevier]

Investigates the abnormalities in the preattentive perception of speech sounds in schizophrenic patients. Level on the amplitude of mismatch negativity for schizophrenic patients; Indication on the weak left temporal combination of current sink and source of schizophrenics; Phase on the occurrence of language-related dysfunction in schizophrenia.

Objective: Many studies have demonstrated mismatch negativity (MMN) attenuation in schizophrenia. Recently, investigators have shown that GABAergic inhibitory neurons may regulate MMN generation. Considering that a substantial proportion of schizophrenic patients receive anxiolytics and hypnotics that have affinity to GABAA receptors to reduce their comorbid symptoms of anxiety and sleep disturbances, we need to assess whether anxiolytics/hypnotics might affect their MMN generation. The aim of this study is to assess the possibility that high or low doses of anxiolytics/hypnotics received by schizophrenic subjects affect their mismatch negativity (MMN), using event-related potentials (ERPs) and magnetoencephalography (MEG).Methods: Twenty-three and 16 patients with schizophrenia participated in the ERP and MEG studies, respectively. Three types of MMN (MMN in response to a duration change of pure-tone stimuli, within-category vowel change (Japanese vowel /a/ with short versus long duration), and across-category vowel change (vowel /a/ versus /o/)) were recorded.Results: High or low doses of benzodiazepine had no significant effects on MMN amplitude/magnetic MMN power, topography/laterality, or latency under any conditions of the ERP or MEG study.Conclusions: These results suggest that chronic administration of anxiolytics/hypnotics does not significantly affect MMN in schizophrenia. [ABSTRACT FROM AUTHOR]

Although many cross-sectional studies showed that psychotic experiences (PEs) and dissociation were closely related, the longitudinal association between them remains unknown. Therefore, the aim of the current study was to examine the longitudinal association of these two symptoms throughout adolescence, under the hypothesis that these two symptoms are bidirectionally associated. Data were obtained from a population-based cohort, the Tokyo Teen Cohort study (TTC; N = 3171). PEs and dissociation were assessed at 10, 12, 14, and 16 years of age. PEs were assessed using a total score from five-item self-report questionnaires derived from the Diagnostic Interview Schedule for Children (DISC-C). Dissociation was assessed using subscale scores of the Child Behavior Checklist (CBCL) completed by primary caregivers. We examined the longitudinal relationship between PEs and dissociation using the random intercept cross-lagged panel model (RI-CLPM). The within-person component of the RI-CLPM revealed no significant cross-lagged effect of dissociation on PEs at any time point. On the other hand, there was a significant (p < 0.05) association between PEs at age 14 and dissociation at age 16 (β = 0.106, 95 % CI 0.047–0.165). The between-person component revealed a significant time-invariant relationship between the two symptoms (β = 0.324, 95 % CI 0.239–0.410). The longitudinal relationship between PEs and dissociation was limited at the within-person level, whereas the between-person correlation was significant. The only significant longitudinal pathway was from PEs to dissociation, suggesting that PEs may be a predictor of dissociation in mid-adolescence. [ABSTRACT FROM AUTHOR]

Near-infrared spectroscopy (NIRS) is a noninvasive functional neuroimaging modality that can detect changes in blood oxygenation levels by tracking cortical neural activity. We recorded the resting-state brain activity of 24 individuals with schizophrenia and 90 healthy controls for 8 min using a whole-head NIRS arrangement and then used partial correlation analysis to estimate the resting-state functional connectivity (RSFC) between 17 cortical regions. We found that the RSFC between the bilateral orbitofrontal cortices (OFCs) and between the right temporal and parietal lobes was significantly higher in patients with schizophrenia than in healthy controls. The RSFC between the bilateral OFCs was positively correlated with negative symptom severity, whereas the RSFC between the right temporal and parietal lobes was positively correlated with the chlorpromazine equivalent for antipsychotics prescribed to patients with schizophrenia. This finding was consistent with that for the RSFC calculated using the anterior 52-channel signals. Our results suggest that NIRS-based RSFC measurements have potential clinical applications. [ABSTRACT FROM AUTHOR]

Background: Understanding the etiology of psychosis is essential to the development of preventive interventions. The COVID‐19 pandemic provides a rare natural experiment that can expand our understanding of the role of social factors in the trajectories and etiology of psychosis across adolescence, particularly in Tokyo where the prevalence of actual COVID‐19 infection remained low. We hypothesized that the likelihood of self‐reporting psychotic experiences (PEs) would increase following the onset of the COVID‐19 pandemic. Methods: The Tokyo Teen Cohort (TTC) is a prospective cohort study of adolescents in the general population of the Tokyo metropolitan area, followed from age 10 to 16 years. We used multi‐level linear regression models to test the associations between the phase of the COVID‐19 pandemic and self‐reported PEs. Results: Among 1935 adolescents included in the analysis, a rapid increase in PEs occurred at the onset of the COVID‐19 pandemic, following approximately 6 years of steady decline across prior waves. This association was more pronounced for boys compared to girls. This increase became more pronounced as the pandemic moved into later phases, defined based on contemporaneous sociopolitical changes in Tokyo (i.e. changes to school closure, social distancing guidelines, and the state of emergency status). Conclusions: The steady decline in PEs across adolescence was halted and reversed concurrent with the COVID‐19 pandemic onset, despite very low rates of COVID‐19 infection. This implicates COVID‐19 related socioenvironmental factors as contributory etiological factors in the development of PEs in this adolescent cohort. [ABSTRACT FROM AUTHOR]

Evidence on the impact of the COVID-19 pandemic on adolescent mental health is mixed and does not disentangle natural age-related changes. We compared depressive symptoms among 16-year-olds surveyed, at a fourth wave, before or during the pandemic, while accounting for expected trajectories of within-person change based on 3 prior waves. In this longitudinal cohort of 3,171 adolescents in Tokyo, Japan, adolescents were grouped based on their age 16 survey timing: pre-pandemic (February 2019 to February 2020) and during-pandemic (March 2020 to September 2021). Depressive symptoms were self-reported using the Short Mood and Feelings Questionnaire. Mixed-effect models were fitted to assess group differences while controlling for previous trends. Variations by sex, household income, and pandemic phase (early, late first-year, and second-year) were examined. Of 2,034 eligible adolescents, 960 (455 girls) were assessed before and 1,074 (515 girls) during the pandemic. Overall, depressive symptoms increased by 0.80 points (95% CI 0.28-1.31, 0.15 SD of the population average). This increase varied by sex and pandemic phase. For boys the increase emerged in the late first-year phase and enlarged in the second-year phase (mean difference from pre-pandemic: 1.69, 0.14-3.24), whereas for girls it decreased in the early school-closure phase (mean difference: –1.98, –3.54 to –0.41) and returned to the pre-pandemic level thereafter, with no additional increases during the pandemic. Into the second year of the COVID-19 pandemic, depressive symptoms of 16-year-olds worsened above the expected age-related change only in boys. Continuous monitoring and preventive approaches for adolescents at the population level are warranted. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. [ABSTRACT FROM AUTHOR]

Background: Little information is available on the association between gender nonconformity during adolescence and subsequent mental health. While the distress related to gender nonconformity may be socially produced rather than attributed to individual-level factors, further research is needed to better understand the role of psychosocial factors in this context. Method: We analyzed data from the Tokyo Teen Cohort, obtained through random sampling of adolescents born between 2002 and 2004. We used inverse probability weighting to examine the association of gender nonconformity at ages 12 and 14 as a time-varying variable with subsequent mental health at age 16, while accounting for time-fixed and time-varying confounders. Furthermore, we used a weighting approach to investigate the mediating role of modifiable psychosocial factors in this association, addressing exposure-mediator and mediator–mediator interactions. Results: A total of 3171 participants were analyzed. Persistent gender nonconforming behavior at ages 12 and 14 was associated with subsequent depression (β = 2.02, 95% confidence interval [CI] 0.85 to 3.19) and psychotic experiences (β = 0.33, 95% CI 0.14 to 0.52) at age 16. The results remained robust in sensitivity analyses. Approximately 30% of the association between gender nonconformity and depression was consistently mediated by a set of psychosocial factors, namely loneliness, bullying victimization, and relationships with mother, father, and friends. Conclusions: Persistent gender nonconformity during adolescence is associated with subsequent mental health. Psychosocial factors play a vital mediating role in this association, highlighting the essential need for social intervention and change to reduce stigmatization and ameliorate mental health challenges. [ABSTRACT FROM AUTHOR]

Gamma oscillations, thought to arise from the activity of ɣ‐aminobutyric acid (GABA)ergic interneurons, have potential as a biomarker for schizophrenia. Gamma‐band auditory steady‐state responses (ASSRs) are notably reduced in both chronic and early‐stage schizophrenia patients. Furthermore, alterations in gamma‐band ASSRs have been demonstrated in animal models through translational research. However, the 40‐Hz harmonic responses of the 20‐Hz ASSR are not as well‐characterized, despite the possibility that these harmonic oscillatory responses may reflect resonant activity in neural circuits. In this study, we investigated the 40‐Hz harmonic response to the 20‐Hz ASSR in the early stages of schizophrenia. The study recruited 49 participants, including 15 individuals at ultra‐high‐risk (UHR) for psychosis, 13 patients with first‐episode schizophrenia (FES), and 21 healthy controls (HCs). The 40‐Hz harmonic responses of the 20‐Hz ASSR were evident in all groups. Interestingly, while previous report observed reduced 40‐Hz ASSRs, the 40‐Hz harmonic responses of the 20‐Hz ASSR were not reduced in the UHR or FES groups. These findings suggest that the gamma‐band ASSR and its harmonic responses may represent distinct aspects of pathophysiology in the early stages of schizophrenia. [ABSTRACT FROM AUTHOR]

Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case–control sample. Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP‐CNVs) in PRKN and examined their association with SCZ and ASD. Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP‐CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP‐CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early‐onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted. [ABSTRACT FROM AUTHOR]

Previous studies have reported that dissociative symptoms (DIS) are associated with self-harm (SH) in adolescents. However, most of these studies were cross-sectional, which limits the understanding of their theoretical relationship. We aimed to investigate the longitudinal relationship between DIS and SH in the general adolescent population. We used data from the Tokyo Teen Cohort study (N = 3007). DIS and SH were assessed at times 1 and 2 (T1 and T2) (12 years of age and 14 years of age, respectively). DIS were assessed using the parent-report Child Behavior Checklist (CBCL), and severe dissociative symptoms (SDIS) were defined as a score above the top 10th percentile. The experience of SH within 1 year was assessed by a self-report questionnaire. The longitudinal relationship between DIS and SH was examined using regression analyses. Using logistic regression analyses, we further investigated the risk for SH at T2 due to persistent SDIS and vice versa. DIS at T1 tended to predict SH at T2 (odds ratio (OR) 1.11, 95% CI 0.99 to 1.25, p = 0.08), while SH at T1 did not predict DIS at T2 (B = − 0.03, 95% CI − 0.26 to 0.20, p = 0.81). Compared with adolescents without SDIS, those with persistent SDIS had an increased risk of SH at T2 (OR 2.61, 95% CI 1.28 to 5.33, p = 0.01). DIS tended to predict future SH, but SH did not predict future DIS. DIS may be a target to prevent SH in adolescents. Intensive attention should be given to adolescents with SDIS due to their increased risk of SH. [ABSTRACT FROM AUTHOR]

Eye movements are indispensable for the collection of visual information in everyday life. Many findings regarding the neural basis of eye movements have been accumulated from neurophysiological and psychophysical studies. In the field of psychiatry, studies on eye movement characteristics in mental illnesses have been conducted since the early 1900s. Participants with schizophrenia are known to have characteristic eye movements during smooth pursuit, saccade control, and visual search. Recently, studies evaluating eye movement characteristics as biomarkers for schizophrenia have attracted considerable attention. In this article, we review the neurophysiological basis of eye movement control and eye movement characteristics in schizophrenia. Furthermore, we discuss the prospects for eye movements as biomarkers for mental illnesses. [ABSTRACT FROM AUTHOR]

Midlife suicide among women has attracted increasing research attention. This study aimed to investigate the longitudinal association between menopause and suicidal ideation among middle-aged women. Our data were derived from the Tokyo Teen Cohort, a population-based survey of early adolescents (N = 3171) and their primary caregivers (typically, mothers) in Japan. A total of 2944 mothers (baseline mean age = 44.0 years) were included in the analysis. The baseline assessment in this study was performed at second-wave survey from July 2014 to January 2017. A follow-up assessment was conducted at fourth-wave survey from February 2019 to September 2021. Suicidal ideation at baseline and follow-up was assessed using the Suicidal Ideation subscale of the 28-item General Health Questionnaire. Menopausal stage was classified based on self-report at fourth-wave survey. Participants who started the perimenopausal stage after baseline were significantly more likely to have suicidal ideation at follow-up than those who did not have experienced menopausal transition yet. Participants with greater social support were less likely to report suicidal ideation at follow-up, even after adjusting for baseline suicidal ideation. This study was based on self-report regarding menopausal stage and only included mothers of adolescents from Japan. An exact length of time from the onset to the presence of suicidal ideation was unavailable. Women who have experienced the onset of menopausal transition presented an increased risk of suicidal ideation. Psychosocial interventions to increase social support may be beneficial in preventing mental health inequalities during menopausal transitions. • A growing number of studies has focused on suicide rates among middle-aged women. • We investigated the relation between menopause and suicidal ideation. • Participants at the perimenopausal stage were more likely to have suicidal ideation. • Greater social support was associated with decreased suicidal ideation at follow-up. • Psychosocial interventions to increase social support may be beneficial. [ABSTRACT FROM AUTHOR]

Long interspersed nuclear element-1 (LINE-1, L1) affects the transcriptome landscape in multiple ways. Promoter activity within its 5'UTR plays a critical role in regulating diverse L1 activities. However, the epigenetic status of L1 promoters in adult brain cells and their relationship with psychiatric disorders remain poorly understood. Here, we examined DNA methylation and hydroxymethylation of the full-length L1s in neurons and nonneurons and identified "epigenetically active" L1s. Notably, some of epigenetically active L1s were retrotransposition competent, which even had chimeric transcripts from the antisense promoters at their 5'UTRs. We also identified differentially methylated L1s in the prefrontal cortices of patients with psychiatric disorders. In nonneurons of bipolar disorder patients, one L1 was significantly hypomethylated and showed an inverse correlation with the expression level of the overlapping gene NREP. Finally, we observed that altered DNA methylation levels of L1 in patients with psychiatric disorders were not affected by the surrounding genomic regions but originated from the L1 sequences. These results suggested that altered epigenetic regulation of the L1 5'UTR in the brain was involved in the pathophysiology of psychiatric disorders. • Epigenetically active L1s were defined in neurons and nonneurons. • Epigenetically active L1s included retrotransposition competent L1s. • L1 inside NREP gene was significantly hypomethyated in bipolar disorder patient. • L1 methylation showed an inverse correlation with NREP expression level. • mC changes of L1s in psychiatric patients were originated from the L1 sequences. [ABSTRACT FROM AUTHOR]

Right auditory cortex dysfunction during musical hallucinations occurred in an 88-year-old woman, who was otherwise cognitively intact. We assessed this phenomenon with a combination of neuromagnetic and cerebral blood-flow measurements. [ABSTRACT FROM AUTHOR]

Background: The 22q11.2 deletion syndrome (22q11DS) is characterised by a changing pattern of overlapping intellectual, physical, and mental disabilities along the course of one's life. However, the impact of overlapping disorders (multimorbidity) on educational challenges remains unclear. Method: A survey was conducted with 88 caregivers of individuals with 22q11DS. A quantitative analysis of educational challenges and support needs divided into age groups (7–12, 13–15, 16–18, and 19 years and over) and a qualitative analysis of the free‐text items in the questionnaire was conducted. Results: Caregivers were more interested in comprehensive developmental support when their children were younger, and the emphasis shifted to concerns regarding environments that matched individual characteristics at older ages. Furthermore, when there are multiple disabilities or disorders, support is concentrated on the more obvious disabilities, and the lack of support for the less superficially obvious disabilities associated with multiple difficulties, including mental health problems, can be a challenge for people with 22q11DS and their families. Conclusions: This study suggests a need for increased focus on multimorbidity and associated disabilities in school education that are difficult to observe because of their mildness or borderline levels if present alone. [ABSTRACT FROM AUTHOR]

Adolescents with high autistic traits are at increased risk of depression. Despite the importance of seeking help for early intervention, evidence on help-seeking intentions amongst this population is scarce. Using a population-based cohort in Japan, we examined adolescents' help-seeking intentions and preferences by the level of autistic traits and tested its mediating role on the association between high autistic traits and depressive symptoms. At age 12, we measured parent-rated autistic traits using the short version of the Autism Spectrum Quotient and classified the adolescents into two groups (≥ 6 as AQhigh, < 6 as AQlow); help-seeking intentions and preferences were assessed through a depression vignette. At age 14, depressive symptoms were self-rated using the Short Mood and Feelings Questionnaire. Hypothesised associations between autistic traits and help-seeking intentions or depressive symptoms were tested applying multivariable regression modelling, while mediation was tested with structural equation modelling. Of the 2505 adolescent participants, 200 (8%) were classified as AQhigh. In both groups, the main source of help-seeking was their family; however, 40% of the AQhigh group reported having no help-seeking intentions compared to 27% in the AQlow. The AQhigh group was at increased risk of not having help-seeking intentions (OR 1.84, 95% CI 1.35–2.50) and higher depressive symptoms (b coefficient 1.06, 0.33–1.79). Help-seeking intentions mediated 18% of the association mentioned above. Interventions to promote help-seeking intentions among adolescents with high autistic traits could reduce their subsequent depressive symptoms. Ideally, such interventions should be provided prior to adolescence and with the involvement of their parents. [ABSTRACT FROM AUTHOR]

There is a well-documented epidemiological association between auditory hallucinations and self-harm in the general population. However, there has been limited research examining specific characteristics of auditory hallucinations (e.g., type, source, or context of voices) as correlates of self-harm. We used prospective data from the Tokyo Teen Cohort to explore whether characteristics of voices reported at age 14 were differentially associated with self-harm behaviors at ages 14 and 16. Among respondents with auditory hallucinations, respondents who experienced voices that "said something bad" about them or commented on their thoughts and actions were most likely to report concurrent self-harm, whereas positive or praising voices were protective. Negative voices continued to predict self-harm two years later, at age 16, even with adjustment for self-harm at age 14. The age of the voices, source of the voices, and context (e.g., falling asleep or while sick) was not associated with likelihood of reporting concurrent or subsequent self-harm behaviors. Assessing for negative voices in particular, rather than auditory hallucinations or psychotic experiences more broadly, may provide a more specific indicator of risk for self-harm among adolescents. The real-world utility of these epidemiological findings should be further examined in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Adolescent loneliness is a growing public health issue owing to its adverse health impact. Although adolescent loneliness is common, its trajectories can show distinct patterns over time. However, there is limited knowledge regarding their determinants, particularly for chronic loneliness. We aimed to determine the predictors of loneliness trajectories across early-to-mid adolescence and examine their association with later suicidality. Methods: Data were collected from 3165 participants from the population-based Tokyo Teen Cohort. Participants reported their loneliness at 10, 12, 14, and 16 years. Loneliness trajectories were identified using latent class growth analysis. We examined the predictive role of bullying victimization and parental psychological distress at age 10 via a multinomial logistic regression. Sociodemographic and child-related factors (i.e., chronic health conditions and cognitive delay) were included as covariates. The association between the trajectories, self-harm, and suicidal ideation by age 16 was investigated using Poisson regression. Results: Four trajectories were identified: "consistently low" (2448, 77.3%), "moderate–decreasing" (185, 5.8%), "moderate–increasing" (508, 16.1%), and "consistently high" (24, 0.8%). Taking "consistently low" as a reference, experiences of bullying victimization predicted all the remaining trajectories [adjusted relative risk ratio 1.64, 95% confidence interval (CI) 1.18–2.28 for "moderate–decreasing," 1.88, 1.52–2.33 for "moderate–increasing," and 4.57, 1.97–10.59 for "consistently high"]. Parental psychological distress predicted the "moderate–increasing" (1.84, 1.25–2.71) and "consistently high" (5.07, 1.78–14.42) trajectories. The "consistently high" trajectory showed the greatest risk for self-harm and suicidal ideation (adjusted relative risk ratio 6.01, 95% CI 4.40–8.22; 2.48, 1.82–3.37, respectively); however, the "moderate–increasing" and "moderate–decreasing" trajectories were also at increased risk (moderate–increasing: 2.71, 2.23–3.30 for self-harm, 1.93, 1.69–2.19 for suicidal ideation; moderate–decreasing: 2.49, 1.91–3.26 for self-harm, 1.59, 1.33–1.91 for suicidal ideation). Conclusions: Bullying victimization and parental psychological distress at age 10 were independent determinants of increased and chronic loneliness trajectories across early-to-mid adolescence. Compared with "consistently low," all other loneliness trajectories were associated with an increased risk of adolescent suicidality. Interventions targeting adolescent loneliness should include approaches to mitigate bullying and parental psychological distress. These strategies may help prevent adolescent suicidality. [ABSTRACT FROM AUTHOR]