Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Distinct Effects of Major Affective Disorder Diagnoses and Suicidal Symptom Severity on Inhibitory Control Function and Proinflammatory Cytokines: Single-Site Analysis of 800 Adolescents and Adults.

BACKGROUND: Inhibitory control function and proinflammatory cytokines play a role in the pathomechanisms underlying major affective disorders and suicidal behavior. However, the distinct or interactive effects of major affective disorders and suicidal symptom severity on inhibitory control function and proinflammatory cytokines remain unclear. METHODS: This study included 287 patients with bipolar disorder, 344 with major depressive disorder, and 169 healthy controls. We categorized the participants into 3 groups based on Montgomery-Åsberg Depression Rating Scale (MADRS) item 10 (suicidal symptoms) score: 0, 2 or 3, and ≥4. The participants completed the go/no-go task and the measurements for C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) levels. RESULTS: Errors in the go/no-go task were associated with suicidality (P = .040), regardless of the severity of suicidal symptoms and diagnosis. An elevated CRP level was especially associated with a Montgomery-Åsberg Depression Rating Scale item 10 score ≥4 (P = .001). An increased TNF-α level could distinguish bipolar disorder from major depressive disorder (P < .001). DISCUSSION: Our study indicated the distinct effects of major affective disorder diagnosis and suicide symptom severity on inhibitory control function and CRP and TNF-α levels. Importantly, individuals with the poorest inhibitory control function and highest CRP levels had more severe suicidal symptoms.

Longitudinal study on all-cause and suicide mortality among individuals with attention deficit hyperactivity disorder.

BACKGROUND: Previous research has linked attention deficit hyperactivity disorder (ADHD) with an increased risk of all-cause mortality, primarily owing to unnatural causes such as accidents and suicides. This increase may be attributable to the co-occurrence of major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), autism spectrum disorder (ASD), anxiety disorders, substance use disorders (SUDs), and personality disorders (PDs). This study examined the all-cause and specific-cause mortality rates in individuals with ADHD and the influence of psychiatric comorbidities. METHODS: Between 2003 and 2017, 1.17 million individuals were enrolled in the study, of which 233,886 received a diagnosis of ADHD from the Taiwan's National Health Insurance Research Database. A 1:4 sex- and birth year-matched control group without ADHD was also included. Hazard ratios (HRs) for mortality rates were estimated between groups after adjusting for demographic data. RESULTS: During the follow-up period, 781 individuals with ADHD died. The HR for all-cause mortality was 1.45 (95% confidence interval [CI]: 1.30-1.61), largely owing to unnatural causes, particularly suicide. Suicide rates were particularly high in individuals with ADHD and psychiatric comorbidities: the HRs for suicide were 47.06 in ADHD with SUDs (95% CI: 6.12-361.99), 32.02 in ADHD with SCZ (7.99-128.29), 23.60 in ADHD with PDs (7.27-76.66), 10.11 in ADHD with anxiety disorders (5.74-17.82), 9.30 in ADHD with BD (4.48-19.33), 8.36 in ADHD with MDD (5.66-12.35), and 6.42 in ADHD with ASD (1.83-22.53) relative to ADHD only. DISCUSSION: ADHD was associated with increased mortality rates, primarily owing to suicide. The presence of major psychiatric comorbidities was associated with a further increase in suicide mortality risk.

Cognition-Modulated Frontal Activity in Prediction and Augmentation of Antidepressant Efficacy: A Randomized Controlled Pilot Study.

Higher rostral anterior cingulate cortex (rACC) activity correlated with frontal theta power (frontalθ) is associated with better antidepressant responses. The antidepressant efficacy of repetitive transcranial magnetic stimulation (rTMS) varied widely; however, the effects of TMS might be modulated by manipulating the pretreatment neural states. Therefore, we conducted a pilot study to investigate whether manipulated frontalθ before rTMS treatment could predict and augment antidepressant responses. A computerized rACC-engaging cognitive task (RECT) was exploited continuously for 10 min to patients with major depressive disorder. In total, 36 patients were randomized to 3 groups (Group-A: RECT[active] + rTMS[active]; Group-B: RECT[sham] + rTMS[active]; Group-C: RECT[active] + rTMS[sham]). Frontalθ and whole-brain glucose uptakes were assessed. We found that the RECT-modulated increases in frontalθ correlated well with rACC glucose uptakes. The treatment responders demonstrated a significant increase in frontalθ after RECT. Post-RECT frontalθ had good sensitivity/specificity in predicting antidepressant responses to rTMS. Group-A had more reduction in total depression scores, had more responders, and was more likely to achieve remission than other groups (Group-A [41.6%] > Group-B [16.6%] > Group-C [0%], P < 0.05). A significant enhancement in the post-1st-rTMS frontalθ was observed in Group-A responders but not in Group-B responders, supporting the argument that RECT-modulated rTMS augmented rTMS efficacy. In conclusion, this study suggests that manipulating pre-rTMS neural activity could predict and augment antidepressant effects to rTMS treatment.

Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study.

Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right-prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness.

Congenital cleft lip and palate and elevated risks of major psychiatric disorders: A nationwide longitudinal study.

BACKGROUND: Congenital cleft lip and palate (CCLP) may be associated with major psychiatric disorders, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, and major depressive disorder. METHODS: From the Taiwan National Health Insurance Research Database, 1,158 children and adolescents with CCLP and 11,580 age/sex-matched controls without CCLP were included in this study between 2001 and 2010; they were followed up until the end of 2011 to identify the aforementioned major psychiatric disorders. RESULTS: After adjustment for age, sex, income, residence, and family history, the Cox regression model revealed a positive relationship of CCLP with subsequent schizophrenia (hazard ratio [HR]: 7.60, 95% confidence interval [CI]: 2.03-28.54), ASD (HR: 6.03, 95% CI: 1.76-20.61), and ADHD (HR: 7.33, 95% CI: 5.01-10.73). DISCUSSION: These findings suggest that clinicians should be attentive to the presence or emergence of mental health conditions in patients with CCLP. Further studies are necessary to investigate the pathogenesis between CCLP and major psychiatric disorders.

Secondary auditory cortex mediates a sensorimotor mechanism for action timing.

The ability to accurately determine when to perform an action is a fundamental brain function and vital to adaptive behavior. The behavioral mechanism and neural circuit for action timing, however, remain largely unknown. Using a new, self-paced action timing task in mice, we found that deprivation of auditory, but not somatosensory or visual input, disrupts learned action timing. The hearing effect was dependent on the auditory feedback derived from the animal's own actions, rather than passive environmental cues. Neuronal activity in the secondary auditory cortex was found to be both correlated with and necessary for the proper execution of learned action timing. Closed-loop, action-dependent optogenetic stimulation of the specific task-related neuronal population within the secondary auditory cortex rescued the key features of learned action timing under auditory deprivation. These results unveil a previously underappreciated sensorimotor mechanism in which the secondary auditory cortex transduces self-generated audiomotor feedback to control action timing.

TNF-α -308 G>A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment.

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.