Current viewpoints on DSM‐5 in Japan

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD‐10) to categorize disorders and determine treatment fees. However, since the publication of the DSM‐III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM‐5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM‐5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive–Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance‐Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.     

Intact working memory in non‐manifesting LRRK2 carriers – an fMRI study

Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non‐manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non‐manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non‐manifesting first‐degree relatives of Parkinson's disease patients (38 carriers). A block‐design fMRI N‐back task, with 0‐back, 2‐back and 3‐back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole‐brain or region‐of‐interest between‐groups differences were found on any of the task conditions. These results indicate that non‐manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N‐back task, remaining relatively intact. These finding shed light on the pre‐motor cognitive changes in this unique ‘at risk’ population and should enable more focused cognitive assessments of these cohorts.     

Prognostic significance of genetic biomarkers in isocitrate dehydrogenase‐wild‐type lower‐grade glioma: the need to further stratify this tumor entity – a meta‐analysis

The clinical outcomes of isocitrate dehydrogenase‐wild‐type (IDH‐wt) lower‐grade glioma (LGG) have been the subject of debate for some time. In this meta‐analysis, we aimed to assess the prognostic values of several known genetic markers (e.g. TERT promoter mutation, H3F3A mutation, CDKN2A loss) in this tumor group. Four electronic databases, including PubMed, Scopus, Web of Science and Virtual Health Library, were searched for relevant articles. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival were calculated using a random‐effect model weighted by an inverse variance method. A total of 11 studies were finally selected from 2274 articles for meta‐analyses. Several genetic alterations were demonstrated to have a negative impact on prognosis of IDH‐wt LGGs, specifically TERT promoter mutation (HR, 1.96; 95% CI, 1.42–2.70), H3F3A mutation (HR, 3.21; 95% CI, 1.86–5.55) and EGFR amplification (HR, 1.67; 95% CI, 1.02–2.74). However, CDKN loss, ATRX mutation and coexisting gain of chromosome 7/loss of chromosome 10 showed no clinical significance in this glioma entity. Our study results demonstrated that IDH‐wt LGGs are heterogeneous in clinical outcome and not all tumors have a poor prognosis. The presence of TERT promoter mutation, H3F3A mutation and EGFR amplification showed negative prognostic impacts in this tumor entity. These genetic events can be used to better stratify patient outcomes.     

Frequency of CNKSR2 mutation in the X‐linked epilepsy‐aphasia spectrum

Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling‐mediated neuronal proliferation, migration and differentiation. Mutations in the X‐linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy‐aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike‐waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X‐linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X‐linked EAS because of the specific genetic counseling implications.     

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Contactin‐associated protein‐like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2‐related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting‐up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage‐gated potassium channel (VGKC) complex that is composed of TAG‐1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up‐to‐date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.     

Heterogeneous neuronal activity in the lateral habenula after short‐ and long‐term cocaine self‐administration in rats

Cocaine addiction is thought to be the result of drug‐induced functional changes in a neural network implicated in emotions, learning and cognitive control. Recent studies have implicated the lateral habenula (LHb) in drug‐directed behavior, especially its aversive aspects. Limited cocaine exposure has been shown to alter neuronal activity in the LHb, but the impact of long‐term drug exposure on habenula function has not been determined. Therefore, using c‐fos as a marker, we here examined neuronal activity in LHb in rats that self‐administered cocaine for either 10 or 60 days. Both the density of labeled cells and the cellular labeling intensity were measured in the lateral (LHbL) and medial (LHbM) parts of LHb. After 10 days of cocaine self‐administration, both the density and intensity of c‐fos‐positive cells were significantly increased in LHbL, but not LHbM, while after 60 days, an increased density (but not intensity) of labeled neurons in both LHbL and LHbM was observed. Most c‐fos‐labeled neurons were glutamatergic. In addition, we found increased GAD65 expression after 10 but not 60 days of cocaine self‐administration in the rostral mesencephalic tegmental nucleus. These data shed light on the complex temporal dynamics by which cocaine self‐administration alters activity in LHb circuitry, which may play an important role in the descent to compulsive drug use as a result of prolonged cocaine‐taking experience.     

Antibodies to cannabinoid type 1 receptor co‐react with stomatin‐like protein 2 in mouse brain mitochondria

Anti‐cannabinoid type 1 receptor (CB₁) polyclonal antibodies are widely used to detect the presence of CB₁ in a variety of brain cells and their organelles, including neuronal mitochondria. Surprisingly, we found that anti‐CB₁ sera, in parallel with CB₁, also recognize the mitochondrial protein stomatin‐like protein 2. In addition, we show that the previously reported effect of synthetic cannabinoid WIN 55,212‐2 on mitochondrial complex III respiration is not detectable in purified mitochondrial preparations. Thus, our study indicates that a direct relationship between endocannabinoid signaling and mitochondrial functions in the cerebral cortex seems unlikely, and that caution should be taken interpreting findings obtained using anti‐CB₁ antibodies.     

Neurones in the Preoptic Area of the Male Goldfish are Activated by a Sex Pheromone 17α,20β‐Dihydroxy‐4‐Pregnen‐3‐One

Pheromones are interesting molecules given their ability to evoke changes in the endocrine state and behaviours of animals. In goldfish, a sex pheromone, 17α,20β‐dihydroxy‐4‐pregnen‐3‐one (17,20β‐P), which is released by preovulatory females, is known to trigger the elevation of luteinising hormone (LH) levels, as well as reproductive behaviour in males. Interestingly, when 11‐ketotestosterone (11‐KT) is implanted into adult female fish, LH levels increase in response to the pheromone at any time of the day, which is normally a male‐specific response. However, the neural mechanisms underlying the male‐specific information processing of 17,20β‐P and its androgen dependence are yet unknown. In the present study, we focused on the preoptic area (POA), which plays important roles in the regulation of reproduction and reproductive behaviours. We mapped activity in the POA evoked by 17,20β‐P exposure using the immediate‐early gene c‐fos. We found that a population of ventral POA neurones close to kisspeptin2 (kiss2) neurones that appear to have important roles in reproduction was activated by 17,20β‐P exposure, suggesting that these activated neurones are important for the 17,20β‐P response. Next, we investigated the distribution of androgen receptor (ar) in the POA and its relationship with 17,20β‐P‐responsive and kiss2 neurones. We found that ar is widely expressed in the ventral POA, whereas it is only expressed in approximately 10% of 17,20β‐P‐activated neurones. On the other hand, it is expressed in almost 90% of the kiss2 neurones. Taken together, it is possible that ar expressing neurones in the ventral POA, most of which were not labelled by c‐fos in the present study, may at least partly account for androgen effects on responses to primer pheromones; the ar‐positive kiss2 neurones in the ventral POA may be a candidate. These results offer a novel insight into the mechanisms underlying male‐specific information processing of 17,20β‐P in goldfish.     

The classic P300 encodes a build‐to‐threshold decision variable

The P300 component of the human event‐related potential has been the subject of intensive experimental investigation across a five‐decade period, owing to its apparent relevance to a wide range of cognitive functions and its sensitivity to numerous brain disorders, yet its exact contribution to cognition remains unresolved. Here, we carry out key analyses of the P300 elicited by transient auditory and visual targets to examine its potential role as a ‘decision variable’ signal that accumulates evidence to a decision bound. Consistent with the latter, we find that the P300 reaches a stereotyped amplitude immediately prior to response execution and that its rate of rise scales with target detection difficulty and accounts for trial‐to‐trial variance in RT. Computational simulations of an accumulation‐to‐bound decision process faithfully captured P300 dynamics when its parameters were set by model fits to the RT distributions. Thus, where the dominant explanatory accounts have conceived of the P300 as a unitary neural event, our data reveal it to be a dynamically evolving neural signature of decision formation. These findings place the P300 at the heart of a mechanistically principled framework for understanding decision‐making in both the typical and atypical human brain.