Shared functional impairment in the prefrontal cortex affects symptom severity across psychiatric disorders.

BACKGROUND: The prefrontal deficits in psychiatric disorders have been investigated using functional neuroimaging tools; however, no studies have tested the related characteristics across psychiatric disorders considering various demographic and clinical confounders. METHODS: We analyzed 1558 functional brain measurements using a functional near-infrared spectroscopy during a verbal fluency task from 1200 participants with three disease spectra [196 schizophrenia, 189 bipolar disorder (BPD), and 394 major depressive disorder (MDD)] and 369 healthy controls along with demographic characteristics (age, gender, premorbid IQ, and handedness), task performance during the measurements, clinical assessments, and medication equivalent doses (chlorpromazine, diazepam, biperiden, and imipramine) in a consistent manner. The association between brain functions and demographic and clinical variables was tested using a general linear mixed model (GLMM). Then, the direction of relationship between brain activity and symptom severity, controlling for any other associations, was estimated using a model comparison of structural equation models (SEMs). RESULTS: The GLMM showed a shared functional deficit of brain activity and a schizophrenia-specific delayed activity timing in the prefrontal cortex (false discovery rate-corrected p < 0.05). Comparison of SEMs showed that brain activity was associated with the global assessment of functioning scores in the left inferior frontal gyrus opercularis (IFGOp) in BPD group and the bilateral superior temporal gyrus and middle temporal gyrus, and the left superior frontal gyrus, inferior frontal gyrus triangularis, and IFGOp in MDD group. CONCLUSION: This cross-disease large-sample neuroimaging study with high-quality clinical data reveals a robust relationship between prefrontal function and behavioral outcomes across three major psychiatric disorders.

The polysemy of psychotropic drugs: continuity and overlap between neuroenhancement, treatment, prevention, pain relief, and pleasure-seeking in a clinical setting.

BACKGROUND: Enhancement involves the use of biomedical technologies to improve human capacities beyond therapeutic purposes. It has been well documented that enhancement is sometimes difficult to distinguish from treatment. As a subtype of enhancement, neuroenhancement aims to improve one's cognitive or emotional capacities. MAIN BODY: This article proposes that the notion of neuroenhancement deserves special attention among enhancements in general, because apart from the notion of treatment, it also overlaps with other concepts such as prevention, pain relief, and pleasure seeking. Regarding prevention, patients' mental endurance can be enhanced when a patient is prescribed a selective serotonin reuptake inhibitor for the purpose of preventing the relapse of depression following a stressful situation. As for pain relief, psychiatrists use medication to alleviate distress in patients who experience various types of anxiety; the alleviation of distress is equal to psychological pain relief, but is also an enhancement of the patient's temperamental traits. Regarding pleasure seeking, insidious transition exists between neuroenhancement and pleasure seeking when using psychotropic drugs. It is well known that people use psychostimulants for recreational purposes and to induce overconfidence in one's performance. The polysemy of psychotropics derives from their effects on human sensibility. Therefore, when using psychotropic agents, psychiatrists should pay close attention to what the agent is used for on each patient in each situation, and explicitly share the continuity and overlap in the purpose of prescribing a medication with the patients to make a better clinical decision. CONCLUSIONS: The notion of neuroenhancement overlaps not only with the notion of treatment, but also with other concepts of prevention, pain relief, and pleasure seeking. The continuity between those concepts makes the issues concerning the prescription of psychotropic drugs subtler. Psychiatrists should explicitly share the continuity with the patients to make a better clinical decision.

Is Utena's Brief Objective Measures (UBOM) useful in real-world behavioral assessment of functioning? Validity and utility testing in patients with schizophrenia.

AIM: Utena's Brief Objective Measures (UBOM) was developed to assess psychophysiological functions proximal to real-world functioning in individuals with psychiatric disorders, including schizophrenia (SCZ), to facilitate shared decision-making. However, the validity of UBOM has not been fully examined. METHODS: We conducted a cross-sectional observational study to evaluate the validity of each of the three tests in UBOM: UBOM-Pulse, UBOM-Ruler, and UBOM-Random. We investigated associations: (i) between UBOM and existing cognitive- and autonomic-function tests; and (ii) between UBOM and daily social functioning. The participants included SCZ individuals and healthy controls. We evaluated the cognitive and autonomic function using UBOM, the heart rate variability test, the simple reaction time test, and the Brief Assessment of Cognition in Schizophrenia, Japanese version. We also assessed the daily social functioning using the WHO Disability Assessment Schedule 2.0 and the modified Global Assessment of Functioning, Japanese version. RESULTS: Thirty-one SCZ individuals and 35 healthy control individuals participated in this study. In the SCZ group, UBOM-Ruler was significantly associated with the Cognition and Getting Along domains of WHO Disability Assessment Schedule 2.0. UBOM-Random was significantly associated with the Brief Assessment of Cognition in Schizophrenia's Working Memory, Verbal Fluency and Attention domains, and the modified Global Assessment of Functioning in the SCZ group. CONCLUSION: The validity of the current version of UBOM is imperfect and further improvements will be necessary to attain the originally intended goal of developing a brief assessment tool for real-world functioning in SCZ.

Identifying neurocognitive markers for outcome prediction of global functioning in individuals with first-episode and ultra-high-risk for psychosis.

AIM: There is an increasing need for identifying neurocognitive predictors of global functional outcome in early psychosis toward optimizing an early intervention strategy. METHODS: We conducted a longitudinal observational study to investigate an association between neurocognitive assessments at baseline and global functional outcome at an average of 1-year follow up. Participants included ultra-high-risk for psychosis (UHR) individuals who had not converted to psychosis during the follow-up period (UHR-NP) and those with first-episode psychosis (FEP). We evaluated neurocognition at baseline using the Brief Assessment of Cognition in Schizophrenia Japanese version, including Verbal Memory, Working Memory, Motor Speed, Verbal Fluency, Attention/Processing Speed, and Executive Function. We also assessed global functional outcome using the modified Global Assessment of Functioning (mGAF) scale both at baseline and after the follow-up period. RESULTS: Thirty-four UHR-NP individuals (34/47, 72%) and 29 FEP individuals (29/36, 81%) completed assessment of neurocognitive function at baseline and functional outcome at follow up. In the UHR-NP group, Attention/Processing Speed was significantly associated with the mGAF score at follow up. In the FEP group, Executive Function was significantly associated with the average mGAF score during follow up. CONCLUSION: Attention/Processing Speed and Executive Function at baseline may predict global functional outcome of early psychosis. These neurocognitive tests are easy to incorporate in clinical settings and, if replicated in independent samples, may be included in routine clinical assessments for prediction of functional outcome in early psychosis.

Detection of resting state functional connectivity using partial correlation analysis: A study using multi-distance and whole-head probe near-infrared spectroscopy.

Multichannel near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that enables easy-to-use and noninvasive measurement of changes in blood oxygenation levels. We developed a clinically-applicable method for estimating resting state functional connectivity (RSFC) with NIRS using a partial correlation analysis to reduce the influence of extraneural components. Using a multi-distance probe arrangement NIRS, we measured resting state brain activity for 8min in 17 healthy participants. Independent component analysis was used to extract shallow and deep signals from the original NIRS data. Pearson's correlation calculated from original signals was significantly higher than that calculated from deep signals, while partial correlation calculated from original signals was comparable to that calculated from deep (cerebral-tissue) signals alone. To further test the validity of our method, we also measured 8min of resting state brain activity using a whole-head NIRS arrangement consisting of 17 cortical regions in 80 healthy participants. Significant RSFC between neighboring, interhemispheric homologous, and some distant ipsilateral brain region pairs was revealed. Additionally, females exhibited higher RSFC between interhemispheric occipital region-pairs, in addition to higher connectivity between some ipsilateral pairs in the left hemisphere, when compared to males. The combined results of the two component experiments indicate that partial correlation analysis is effective in reducing the influence of extracerebral signals, and that NIRS is able to detect well-described resting state networks and sex-related differences in RSFC.

Characterizing prefrontal cortical activity during inhibition task in methamphetamine-associated psychosis versus schizophrenia: a multi-channel near-infrared spectroscopy study.

Methamphetamine abuse and dependence, frequently accompanied by schizophrenia-like psychotic symptoms [methamphetamine-associated psychosis (MAP)], is a serious public health problem worldwide. Few studies, however, have characterized brain dysfunction associated with MAP, nor investigated similarities and differences in brain dysfunction between MAP and schizophrenia. We compared prefrontal cortical activity associated with stop-signal inhibitory task in 21 patients with MAP, 14 patients with schizophrenia and 21 age- and gender-matched healthy controls using a 52-channel near-infrared spectroscopy (NIRS) system. Both the MAP and the schizophrenia groups showed significantly reduced activation in the bilateral ventrolateral prefrontal cortex compared with controls; however, only the MAP group showed reduced activation in the frontopolar prefrontal cortex. The MAP group demonstrated significant positive correlations between task performance and hemodynamic responses in the bilateral ventrolateral, polar and left dorsolateral regions of the prefrontal cortex. The MAP and schizophrenia groups demonstrated a significant difference in the relationship of impulsivity to hemodynamic changes in the bilateral premotor cortex. These findings characterize similarities and differences in prefrontal cortical dysfunction between psychosis associated with methamphetamine and schizophrenia. The reduced hemodynamic changes in the bilateral ventrolateral prefrontal cortex suggest a common underlying pathophysiology of MAP and schizophrenia, whereas those in the frontopolar prefrontal cortex point to an impaired state that is either inherent or caused specifically by methamphetamine use.

Development of a neurofeedback protocol targeting the frontal pole using near-infrared spectroscopy.

AIM: Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. METHODS: We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. RESULTS: Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). CONCLUSION: The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation.

Genetic influences on prefrontal activation during a verbal fluency task in adults: a twin study based on multichannel near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) studies have reported that prefrontal hemodynamic dysfunction during executive function tasks may be a promising biomarker of psychiatric disorders, because its portability and noninvasiveness allow easy measurements in clinical settings. Here, we investigated the degree to which prefrontal NIRS signals are genetically determined. Using a 52-channel NIRS system, we monitored the oxy-hemoglobin (oxy-Hb) signal changes in 38 adult pairs of right-handed monozygotic (MZ) twins and 13 pairs of same-sex right-handed dizygotic (DZ) twins during a letter version of the verbal fluency task. Heritability was estimated based on a classical twin paradigm using structured equation modeling. Significant genetic influences were estimated in the right dorsolateral prefrontal cortex and left frontal pole. The degrees of heritability were 66% and 75% in the variances, respectively. This implies that the prefrontal hemodynamic dysfunction observed during an executive function task measured by NIRS may be an efficient endophenotype for large-scale imaging genetic studies in psychiatric disorders.

Chronic periodic lateralised epileptic discharges and anti-N-methyl-D-aspartate receptor antibodies.

Periodic lateralised epileptiform discharges (PLEDs) are uncommon transient electroencephalographic findings accompanied by acute brain lesions. A small proportion of PLEDs persist for more than three months and are called "chronic" PLEDs, the pathophysiology of which is still debated. Herein, we report a man with right hemispheric PLEDs which lasted for more than 14 months and mild left hemispatial neglect after he experienced status epilepticus. Although MRI was normal, positron emission tomography revealed right temporo-parieto-occipital hypometabolism, which coincided with the source area of PLEDs estimated by magnetoencephalography. In addition, levels of anti-N-methyl-D-aspartate (NMDA) receptor antibodies and granzyme B were found to be high in the cerebrospinal fluid. Following two courses of steroid pulse therapy, the patient's left spatial neglect improved and the PLEDs were partially resolved. These findings suggest that the chronic PLEDs present in this case were an interictal phenomenon and that their pathophysiology involved autoimmune processes.

Abnormal resting-state hyperconnectivity in schizophrenia: A whole-head near-infrared spectroscopy study.

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.

Epistemic injustice in the therapeutic relationship in psychiatry.

The notion of epistemic injustice was first applied to cases of discrimination against women and people of color but has since come to refer to wider issues related to social justice. This paper applies the concept of epistemic injustice to problems in the therapeutic relationship between psychiatrists and psychiatric patients. To this end, it is necessary to acknowledge psychiatrists as professionals with expertise in treating mental disorders, which impair the patient's rationality, sometimes leading to false beliefs, such as delusions. This paper classifies the characteristic features of the therapeutic relationship in psychiatry into three stages: those of a professional-client relationship, those of a doctor-patient relationship, and those of a psychiatrist-psychiatric patient relationship. Epistemic injustice is prevalent in psychiatric care owing to prejudice against patients with mental disorders. However, it is also predisposed by the roles that psychiatrists play in relation to psychiatric patients. This paper suggests some ameliorative measures based on the analysis.

A case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) coexisting with pervasive developmental disorder harboring SCN1A mutation in addition to CHRNB2 mutation.

We report a case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with several characteristics distinct from previously reported cases, in which genetic studies identified mutations in two different genes. This case differed from typical ADNFLE with respect to the following: (1) slightly younger onset and refractory to antiepileptic drugs and (2) borderline intellectual functioning and coexistence of pervasive developmental disorder from infancy. Genetic testing revealed a novel mutation and a silent substitution in SCN1A (c.4285G>T, A1429S and c.4371G>C, silent) in addition to a known mutation in CHRNB2 (c.1200C>G, I312M). SCN1A is a gene that codes for the voltage-dependent sodium channel α1 subunit and has been implicated in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy in infancy. However, the relation between SCN1A and ADNFLE is unknown. We report the clinical course and symptomatic characteristics of this case although the relationship between ADNFLE mutation and SCN1A mutation remains to be elucidated.

Acute psychosis during the postictal period in a patient with idiopathic generalized epilepsy: postictal psychosis or aggravation of schizophrenia? A case report and review of the literature.

Postictal psychoses are common comorbid conditions of temporal lobe epilepsy and are reported to be characterized by affective changes. However, postictal psychoses are rare among patients with idiopathic generalized epilepsy, and the causal relationship between postictal psychoses and idiopathic generalized epilepsy is unknown. Here, we report the case of a man who had idiopathic generalized epilepsy and experienced 4 episodes of schizophrenia-like interictal psychosis before the age of 41 years. At the age of 56 years, he experienced a generalized tonic-clonic seizure for the first time in 15 years and developed psychotic symptoms on the next day. Notably, in addition to the schizophrenia-like symptoms, the patient experienced mania-like symptoms such as elated mood, grandiose delusions, agitation, and pressured speech during the last psychotic episode in the postictal period. It was suspected that postictal neuronal processes and a predisposition to endogenous psychosis both contributed to the psychopathology of this episode.

Retrospective chart review-based assessment scale for adverse childhood events and experiences.

Aim: Adverse childhood experiences (ACEs) are highly prevalent in the general population, and their lifelong impact on physical and mental health is profound. In assessing ACEs, it is vital to consider the pathways and modalities by which an individual internalizes events as an adverse experience and its effects on their biological, psychological, and social function. However, conventional assessments of ACEs are inadequate in that they do not comprehensively assess the source of the adverse event and the pathway and mode of its impact on the individual. Methods: This study developed an original scale for ACEs that classifies the source of the event and the pathway and mode of its impact on the individual from a retrospective review of medical charts. We also used this scale to investigate the ACEs in 536 patients with psychiatric disorders (depression, bipolar disorder, and schizophrenia). Results: This scale consisted of 28 items, and its reliability and validity were sufficient. We also found that 45.9% of the patients studied had at least one ACE, ranging from 43.5% to 51.5% for all disorders. Psychological trauma (bullying) from peers was the most common cause at 27.2%. Conclusion: We developed a retrospective chart review-based assessment tool for ACEs which enables the examination of the source of the events of ACEs and the pathways and modalities of their impact on the individual. The frequency of ACEs is high regardless of the type of psychiatric disorder, and horizontal trauma (bullying victimization) is as frequent as vertical trauma (parental maltreatment).

Personalized values in life as point of interaction with the world: Developmental/neurobehavioral basis and implications for psychiatry.

Behavioral neuroscience has dealt with short-term decision making but has not defined either daily or longer-term life actions. The individual brain interacts with the society/world, but where that point of action is and how it interacts has never been an explicit scientific question. Here, we redefine value as an intrapersonal driver of medium- and long-term life actions. Value has the following three aspects. The first is value as a driving force of action, a factor that commits people to take default-mode or intrinsic actions daily and longer term. It consists of value memories based on past experiences, and a sense of values, the source of choosing actions under uncertain circumstances. It is also a multilayered structure of unconscious/automatic and conscious/self-controlled. The second is personalized value, which focuses not only on the value of human beings in general, but on the aspect that is individualized and personalized, which is the foundation of diversity in society. Third, the value is developed through the life course. It is necessary to clarify how values are personalized through the internalization of parent-child, peer, and social experiences through adolescence, a life stage almost neglected in neuroscience. This viewpoint describes the brain and the behavioral basis of adolescence in which the value and its personalization occur, and the importance of this personalized value as a point of interaction between the individual brain and the world. Then the significance of personalized values in psychiatry is discussed, and the concept of values-informed psychiatry is proposed.

Abnormality of Resting-State Functional Connectivity in Major Depressive Disorder: A Study With Whole-Head Near-Infrared Spectroscopy.

Near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that has advantages in clinical usage. Previous functional magnetic resonance imaging (fMRI) studies have found that the resting-state functional connectivity (RSFC) of the default mode network (DMN) is increased, while the RSFC of the cognitive control network (CCN) is reduced in patients with major depressive disorder (MDD) compared with healthy controls. This study tested whether the NIRS-based RSFC measurements can detect the abnormalities in RSFC that have been associated with MDD in previous fMRI studies. We measured 8 min of resting-state brain activity in 34 individuals with MDD and 78 age- and gender-matched healthy controls using a whole-head NIRS system. We applied a previously established partial correlation analysis for estimating RSFCs between the 17 cortical regions. We found that MDD patients had a lower RSFC between the left dorsolateral prefrontal cortex and the parietal lobe that comprise the CCN, and a higher RSFC between the right orbitofrontal cortex and ventrolateral prefrontal cortex, compared to those in healthy controls. The RSFC strength of the left CCN was negatively correlated with the severity of depressive symptoms and the dose of antipsychotic medication and positively correlated with the level of social functioning. The results of this study suggest that NIRS-based measurements of RSFCs have potential clinical applications.

Surface area in the insula was associated with 28-month functional outcome in first-episode psychosis.

Many studies have tested the relationship between demographic, clinical, and psychobiological measurements and clinical outcomes in ultra-high risk for psychosis (UHR) and first-episode psychosis (FEP). However, no study has investigated the relationship between multi-modal measurements and long-term outcomes for >2 years. Thirty-eight individuals with UHR and 29 patients with FEP were measured using one or more modalities (cognitive battery, electrophysiological response, structural magnetic resonance imaging, and functional near-infrared spectroscopy). We explored the characteristics associated with 13- and 28-month clinical outcomes. In UHR, the cortical surface area in the left orbital part of the inferior frontal gyrus was negatively associated with 13-month disorganized symptoms. In FEP, the cortical surface area in the left insula was positively associated with 28-month global social function. The left inferior frontal gyrus and insula are well-known structural brain characteristics in schizophrenia, and future studies on the pathological mechanism of structural alteration would provide a clearer understanding of the disease.

Prefrontal dysfunction associated with a history of suicide attempts among patients with recent onset schizophrenia.

Suicide is a major cause of death in patients with schizophrenia, particularly among those with recent disease onset. Although brain imaging studies have identified the neuroanatomical correlates of suicidal behavior, functional brain activity correlates particularly in patients with recent-onset schizophrenia (ROSZ) remain unknown. Using near-infrared spectroscopy (NIRS) recording with a high-density coverage of the prefrontal area, we investigated whether prefrontal activity is altered in patients with ROSZ having a history of suicide attempts. A 52-channel NIRS system was used to examine hemodynamic changes in patients with ROSZ that had a history of suicide attempts (n = 24) or that lacked such a history (n = 62), and age- and sex-matched healthy controls (n = 119), during a block-design letter fluency task (LFT). Patients with a history of suicide attempts exhibited decreased activation in the right dorsolateral prefrontal cortex compared with those without such a history. Our findings indicate that specific regions of the prefrontal cortex may be associated with suicidal attempts, which may have implications for early intervention for psychosis.