Cerebral activation caused by dental sounds: a functional magnetic resonance imaging study.

Dental drilling sounds can induce anxiety in some patients. This study aimed to use functional magnetic resonance imaging (fMRI) to assess the relationship between dental fear and auditory stimuli. Thirty-four right-handed individuals (21 women and 13 men; average age, 31.2 years) were selected. The level of dental fear was assessed using the dental fear survey (DFS). Based on a threshold DFS score > 52, participants were categorized into two groups: dental fear (DF) group (n = 12) and control group (n = 22). Two types of stimuli were presented in a single session: dental and neutral sounds. Cerebral activation during the presentation of these sounds was evaluated using contrast-enhanced blood oxygenation level-dependent fMRI. In the DF group, dental sounds induced significantly stronger activation in the left inferior frontal gyrus and left caudate nucleus (one-sample t test, P < 0.001). In contrast, in the control group, significantly stronger activation was observed in the bilateral Heschl's gyri and left middle frontal gyrus (one-sample t test, P < 0.001). Additionally, a two-sample t test revealed that dental sounds induced a significantly stronger activation in the left caudate nucleus in the DF group than in the control group (P < 0.005). These findings suggest that the cerebral activation pattern in individuals with DF differs from that in controls. Increased activation of subcortical regions may be associated with sound memory during dental treatment.

Prediction of Corresponding Dose of Transdermal Blonanserin to Oral Dose Based on Dopamine D2 Receptor Occupancy: Unique Characteristics of Blonanserin Transdermal Patch.

BACKGROUND/PURPOSE: Blonanserin is an atypical antipsychotic, a potent selective antagonist of dopamine D2 receptor (D2), prescribed as oral formulations in patients with schizophrenia. Blonanserin transdermal patch was developed to provide a new treatment option, but the corresponding dose to oral blonanserin was not clear. The aims of this study were to clarify the pharmacokinetic (PK)-pharmacodynamic characteristics of blonanserin after transdermal patch application and to evaluate the corresponding dose to oral formulation based on striatal D2 occupancy. METHODS: The relationship between D2 occupancy and plasma blonanserin concentration was analyzed using an Emax model based on data from positron emission tomography study with oral and transdermal blonanserin. D2 occupancy was simulated using Emax models based on the observed plasma concentrations and the simulated plasma concentrations obtained from population PK model. RESULTS: Plasma blonanserin concentration levels after repeated patch applications were nearly stable throughout the day and no effect of sex, advanced age, or application site was detected. The concentration at half maximal D2 occupancy during transdermal patch applications, 0.857 ng/mL, was higher than that after oral doses, 0.112 ng/mL, suggesting metabolite contribution after oral doses. The median predicted D2 occupancy during blonanserin patch applications at doses of 40 and 80 mg/d was 48.7% and 62.5%, respectively, and the distribution of D2 occupancy at these doses could cover most of that at oral doses of 8 to 24 mg/d. CONCLUSIONS: Predicted D2 occupancy suggested that a 40- to 80-mg/d blonanserin transdermal patch dose corresponds to an 8- to 24-mg/d oral dose for the treatment of schizophrenia.

Suicide decline and improved psychiatric treatment status: longitudinal survey of suicides and serious suicide attempters in Tokyo.

BACKGROUND: Connecting individuals in need of psychiatric treatment with adequate medical services has been a major strategy for suicide prevention in Japan. By investigating serious suicide attempters admitted to our Critical Care Medical Center (CCM), we aimed to examine longitudinal changes in the psychiatric treatment status of high-risk suicidal individuals, and to explore the association between any improvement in psychiatric treatment status and suicide decline. METHODS: Subjects from two periods, 2006-2011 and 2012-2017, were enrolled. We collected the data of 32,252 suicides in Tokyo from police reports and the data of 942 suicide attempters admitted to CCM from medical records. Data were annually collected by both age and gender for the number of suicide completers, the number of suicide attempters, and the psychiatric treatment rates, respectively. ANOVA and t-test were used to examine whether there were differences in the number of suicides and attempers between the two periods. The difference in psychiatric treatment rate between the two periods was examined by chi-square test. Additionally, we used Pearson's correlation coefficient to analyze any correlation between annual treatment rate and the number of suicide completers in subgroups with altered psychiatric treatment rates. RESULTS: The number of suicide attempters in the 20-39-year age group of decreased together with the number of suicides. Psychiatric treatment rates of male attempters aged 20-59 years improved significantly from 48.7 to 70.6% and this improvement correlated with a decrease in suicides. However, psychiatric treatment rates in the elderly, which have the highest number of suicides in both genders, did not improve and remain low. CONCLUSIONS: The number of suicide attempters, as well as that of suicides, decreased in Tokyo. Improvement of psychiatric treatment status in high-risk suicidal male adults may have contributed to the reduction of suicides in Tokyo. However, the continuing low rate of psychiatric treatment in the elderly is a pressing issue for future suicide prevention.

Striatal Dopamine D2 Receptor Occupancy Induced by Daily Application of Blonanserin Transdermal Patches: Phase II Study in Japanese Patients With Schizophrenia.

BACKGROUND: Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application. METHODS: This open-label, phase II study enrolled 18 Japanese outpatients (20 to <65 years) with schizophrenia (DSM-IV-TR criteria; total Positive and Negative Syndrome Scale score <120 at screening) treated with blonanserin 8-mg or 16-mg tablets. Patients continued tablets for 2-4 weeks at their current dose and were then assigned to once-daily blonanserin patches (10/20/40/60/80 mg daily) for 2-4 weeks based on the oral dose. [11C]raclopride positron emission tomography scanning determined blonanserin striatal dopamine D2 receptor occupancy (primary endpoint). Secondary endpoints included assessment of receptor occupancy by dose, changes in Positive and Negative Syndrome Scale and Clinical Global Impressions-Severity of Illness-Severity scores, patient attitudes towards adherence, and patch adhesiveness. RESULTS: Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns. CONCLUSIONS: Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia. TRIAL REGISTRY: JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).

Effects of anodal transcranial direct current stimulation on implicit motor learning and language-related brain function: An fMRI study.

AIM: Anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) is known as a useful application for improving depressive symptoms or cognitive performance. Antidepressive effects by anodal tDCS over the left DLPFC are expected, but the neural mechanisms of these effects are still unclear. Further, in depression, reduced performance and left prefrontal hypofunction during the verbal fluency task (VFT) are generally known. However, few studies have examined the effect of tDCS on the language-related cerebral network. We aimed to investigate whether anodal tDCS at the left DLPFC affects cognitive performance and the neural basis of verbal fluency. METHODS: Nineteen healthy volunteers participated in this study. The effects of tDCS on cognitive behavior and cerebral function were evaluated by (i) performance and accuracy of implicit/explicit motor learning task (serial reaction time task/sequential finger-tapping task), and (ii) cerebral activation while the subjects were performing the VFT by using a functional MRI protocol of a randomized sham-controlled, within-subjects crossover design. RESULTS: Reaction times of the implicit motor learning task were significantly faster with tDCS in comparison with the sham. Further, language-related left prefrontal-parahippocampal-parietal activation was significantly less with tDCS compared with the sham. Significant correlation was observed between shortened response time in serial reaction time task and decreased cerebral activation during VFT with tDCS. CONCLUSION: Anodal tDCS over the left DLPFC could improve cognitive behavior of implicit motor learning by improving brain function of the frontoparietal-parahippocampal region related to motor learning, as well as language-related regions.

Psychometric properties of the Japanese version of the Geriatric Anxiety Inventory for community-dwelling older adults.

BACKGROUND: This study developed a Japanese version of the Geriatric Anxiety Inventory (GAI-J) and its short form (GAI-J-SF) to evaluate anxiety in older adults in Japan and assess these measures' psychometric properties with a cross-sectional design. METHODS: Participants (N = 400; mean age: 75 years) were community-dwelling older adults who answered a set of self-report questionnaires. They were recruited from a community centre for older persons in the Kanto region of Japan. Of the respondents, 100 participated in a follow-up survey to evaluate test-retest reliability. Item response theory was adopted to evaluate item parameters. RESULTS: Confirmatory factor analysis with categorical data suggested that, as with the original Geriatric Anxiety Inventory, the GAI-J/GAI-J-SF had a unifactor structure. Test-retest correlation and internal consistency analyses indicated that these scales had high reliability. Item response theory results showed that both measures' item parameters were acceptable. Correlations with the Penn State Worry Questionnaire, State Trait Anxiety Inventory-State Only, Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 were mostly consistent with our hypotheses. This supports the high convergent validity of the GAI-J/GAI-J-SF. CONCLUSIONS: The findings indicate that the GAI-J and the GAI-J-SF have robust psychometric properties for assessing late-life anxiety in older Japanese adults. Future GAI-J studies in clinical groups are needed.

Low dopamine transporter binding in the nucleus accumbens in geriatric patients with severe depression.

AIM: Dysfunction of dopaminergic neurons in the central nervous system is considered to be related to major depressive disorder (MDD). Especially, MDD in geriatric patients is characterized by anhedonia, which is assumed to be associated with reduced dopamine neurotransmission in the reward system. Dopamine transporter (DAT) is considered to reflect the function of the dopamine nerve system. However, previous DAT imaging studies using single photon emission computed tomography or positron emission tomography (PET) have shown inconsistent results. The radioligand [18 F]FE-PE2I for PET enables more precise evaluation of DAT availability. Hence, we aimed to evaluate the DAT availability in geriatric patients with MDD using [18 F]FE-PE2I. METHODS: Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [18 F]FE-PE2I, which has high affinity and selectivity for DAT. Binding potentials (BPND ) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BPND values were compared between MDD patients and healthy controls. RESULTS: MDD patients showed significantly lower DAT BPND in the NAc (P = 0.009), and there was a trend of lower BPND in the putamen (P = 0.032) compared to controls. CONCLUSION: We found low DAT in the NAc and putamen in geriatric patients with severe MDD, which could be related to dysregulation of the reward system.

Comparison of Dopamine D3 and D2 Receptor Occupancies by a Single Dose of Blonanserin in Healthy Subjects: A Positron Emission Tomography Study With [11C]-(+)-PHNO.

Background: Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects. Methods: Six healthy males (mean 35.7±7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO. Results: Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%-81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4%-84.3%; mean±SD, 73.3%±8.2%), ventral striatum (range 40.1%-88.2%; mean±SD, 60.8%±17.1%), globus pallidus (range 65.8%-87.6%; mean±SD, 75.7%±8.6%), and substantia nigra (range 56.0%-88.7%; mean±SD, 72.4%±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79). Conclusions: A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.

Japanese multicenter database of healthy controls for [123I]FP-CIT SPECT.

PURPOSE: The aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan. METHODS: This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30-83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom. RESULTS: The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30-39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70-79 age group. CONCLUSIONS: This study provided a large-scale quantitative database of [123I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database.

Amyloid imaging with [(18)F]florbetapir in geriatric depression: early-onset versus late-onset.

BACKGROUND: We examined patients with mild cognitive impairment (MCI) with a history of geriatric depression (GD) and healthy controls (HC) to evaluate the effect of beta-amyloid (Aß) pathology on the pathology of GD by using [(18)F]florbetapir PET. METHODS: Thirty-three elderly patients (76.7 ± 4.2 years) and 22 healthy controls (HC; 72.0 ± 4.5 years, average ± SD) were examined by [(18)F]florbetapir positron emission tomography (PET) to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI to determine the degree of atrophy, by Mini-Mental State Examination for cognitive functions, and by Geriatric Depression Scale for the severity of depression, and by Clinical Dementia Rating for activity of daily living (ADL). The cut-off value of 1.08 for SUVR was defined as Aß-positive. RESULTS: Of the patients and HC, 39.4% and 27.3%, respectively, were beta-amyloid-positive. The onset age of GD was significantly correlated with SUVR (r = 0.44, p < 0.01). Compared to patients without Aß (GD-Aß), patients with Aß (GD + Aß) did not differ in terms of age, cognitive function, severity of depression and ADL, and brain atrophy. GD + Aß had significantly older average ± SD age at onset of GD (73.6 ± 7.1 versus 58.7 ± 17.8, p < 0.01) and significantly shorter average ± SD time between onset of GD and PET scan day (3.1 ± 5.2 years versus 18.1 ± 18.6 years, p < 0.001) than GD-Aß. CONCLUSIONS: Our results showed that the rate of Aß positivity was higher in late-onset GD and that onset-age was associated with SUVR, suggesting that the later the onset of GD, the more Aß pathology affected its onset.

Comparison of imaging biomarkers for Alzheimer's disease: amyloid imaging with [18F]florbetapir positron emission tomography and magnetic resonance imaging voxel-based analysis for entorhinal cortex atrophy.

OBJECTIVE: We compared amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) in subjects clinically diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHC) in order to test how these imaging biomarkers represent cognitive decline in AD. METHODS: Fifteen OHC, 19 patients with MCI, and 19 patients with AD were examined by [(18)F]florbetapir PET to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI and the voxel-based specific regional analysis system for AD to calculate z-score as the degree of entorhinal cortex atrophy, and by mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive component--Japanese version (ADAS-Jcog) for cognitive functions. RESULTS: Both cutoff values for measuring AD-like levels of amyloid (1.099 for SUVR) and entorhinal cortex atrophy (1.60 for z-score) were well differentially diagnosed and clinically defined AD from OHC (84.2% for SUVR and 86.7% for z-score). Subgroup analysis based on beta-amyloid positivity revealed that z-score significantly correlated with MMSE (r = -0.626, p < 0.01) and ADAS-Jcog (r = 0.691, p < 0.01) only among subjects with beta-amyloid. CONCLUSIONS: This is the first study to compare [(18)F]florbetapir PET and MRI voxel-based analysis of entorhinal cortex atrophy for AD. Both [(18)F]florbetapir PET and MRI detected changes in AD compared with OHC. Considering that entorhinal cortex atrophy correlated well with cognitive decline only among subjects with beta-amyloid, [18F]florbetapir PET makes it possible to detect AD pathology in the early stage, whereas MRI morphometry for subjects with beta-amyloid provides a good biomarker to assess the severity of AD in the later stage.

In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [¹8F]FE-PE2I.

Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300 mg) in ten healthy volunteers using positron emission tomography (PET) with [¹8F]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200 mg and 56.9% at 300 mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission.

Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB.

Tramadol is used for the treatment of pain, and it is generally believed to activate the µ-opioid receptor and inhibit serotonin (5-HT) and norepinephrine (NE) transporters. Recent findings from animal experiments suggest that 5-HT reuptake inhibition in brain is related to pain reduction. However, there has been no report of 5-HT transporter (5-HTT) occupancy by tramadol at clinical doses in humans. In the present study, we investigated 5-HTT occupancy by tramadol in five subjects receiving various doses of tramadol by using positron emission tomography (PET) scanning with the radioligand [11C]DASB. Our data showed that mean 5-HTT occupancies in the thalamus by single doses of tramadol were 34.7% at 50 mg and 50.2% at 100 mg. The estimated median effective dose (ED50) of tramadol was 98.1 mg, and the plasma concentration was 0.33 µg/ml 2 h after its administration; 5-HTT occupancy by tramadol was dose-dependent. We estimated 5-HTT occupancy at 78.7% upon taking an upper limit dose (400 mg) of tramadol. The results of the present study support the finding that 5-HTT inhibition is involved in the mechanism underlying the analgesic effect of tramadol in humans, and a clinical dose of tramadol sufficiently inhibits 5-HTT reuptake; this inhibition is similar to that shown by selective serotonin reuptake inhibitors (SSRIs).

Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹8F]FMeNER-D2 to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED50) and concentration (EC50) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Delayed Diagnosis of Painless Thyroiditis in an Adolescent Presenting with Aggression and Disruptive Behavior Initially Attributed to Worsening of a Psychiatric Disorder.

Painless thyroiditis, which is rare in children, exhibits the characteristic sequence of hyperthyroidism, including aggressive and disruptive behaviors. Unlike subacute thyroiditis or Graves' disease, painless thyroiditis is challenging to diagnose because of its mild symptoms and minimal or absent physical findings. Moreover, aggressive and disruptive behaviors in children with psychiatric disorders may be misconstrued as exacerbation of underlying symptoms. The present patient was a 16-year-old male with adjustment disorder who presented to a pediatric psychiatric clinic for assessment of irritability. After 4 months, he developed aggressive and disruptive behaviors that prompted initiation of risperidone but without improvement. After 1 month, he reported palpitations and dyspnea. His neck was supple and non-tender without thyroid enlargement. Thyroid studies revealed elevated free T4 and T3 levels and suppressed thyroid-stimulating hormone level, suggesting hyperthyroidism. A radioactive iodine uptake test revealed a barely visible thyroid gland, consistent with thyroiditis. Painless thyroiditis, without thyroid tenderness, was diagnosed. We describe a case of painless thyroiditis in an adolescent patient with aggressive and disruptive behaviors that were initially attributed to worsening of an underlying adjustment disorder. Even when minimal or no signs of hyperthyroidism are present, painless thyroiditis should be considered in the differential diagnosis of children with aggressive and disruptive behaviors. Awareness of potential anchoring bias is also recommended to prevent its delayed diagnosis of such behaviors.

Tramadol Effects on Brain Activity During Cognitive and Emotional Empathy for Pain: A Randomized Controlled Study.

Pain is perceived not only by personal experience but also vicariously. Pain empathy is the ability to share and understand other's intentions and emotions in their painful conditions, which can be divided into cognitive and emotional empathy. It remains unclear how centrally acting analgesics would modulate brain activity related to pain empathy and which component of pain empathy would be altered by analgesics. In this study, we examined the effects of the analgesic tramadol on the brain activity for pain empathy in healthy adults. We used 2 tasks to assess brain activity for pain empathy. In experiment 1, we used a well-established picture-based pain empathy task involving passive observation of other's pain. In experiment 2, we developed a novel pain empathy task to assess brain activity during cognitive and emotional empathy for pain separately in a single task. We conducted a double-blind, placebo-controlled within-subject crossover study with functional magnetic resonance imaging for 33 participants in experiment 1 and 31 participants in experiment 2, respectively. In experiment 1, we found that tramadol decreased activation in the supramarginal gyrus during observation of other's pain compared with placebo. Supramarginal gyrus activation correlated negatively with the thermal pain threshold. In experiment 2, we found that tramadol decreased activation in angular gyrus in cognitive empathy for pain compared with placebo but did not change brain activity in emotional empathy for pain. PERSPECTIVE: Centrally acting analgesics such as tramadol may have not only analgesic effects on self-experienced pain but also on the complex neural processing of pain empathy.

A randomized placebo controlled trial demonstrates the effect of dl-methylephedrine on brain functions is weaker than that of pseudoephedrine.

Intellectual drug doping in athletics by using stimulants that affect central nervous system functions has been diversified. Stimulants are regulated by the World Anti-Doping Agency according to their levels of urinary concentration. Positron emission tomography could evaluate how stimulants affect central nervous system functions. We aimed to evaluate the effect of stimulants on brain function by examining the difference in brain dopamine transporter occupancy by PET after administration of dl-methylephedrine or pseudoephedrine at the clinical maximum daily dose. Four PET scans without and with drug administration (placebo, dl-methylephedrine 150 mg and pseudoephedrine 240 mg) were performed. The concentrations of dl-methylephedrine and pseudoephedrine in plasma and urine were measured. DAT occupancies in the striatum with placebo, dl-methylephedrine and pseudoephedrine were calculated by PET images. The urinary concentration of dl-methylephedrine (12.7 µg/mL) exceeded the prohibited concentration (10 µg/mL), but the DAT occupancy with dl-methylephedrine (6.1%) did not differ (p = 0.92) from that with placebo (6.2%). By contrast, although the urinary concentration of pseudoephedrine (144.8 µg/mL) was below the prohibited concentration (150 µg/mL), DAT occupancy with pseudoephedrine was 18.4%, which was higher than that with placebo (p = 0.009). At the maximum clinical dose, dl-methylephedrine was shown to have weaker effects on brain function than pseudoephedrine.

New-onset schizophrenia in an adolescent after COVID-19.

Schizophrenia develops during adolescence. Maternal infections during the fetal period increase the incidence of schizophrenia in children, which suggests that the pathogenesis involves neuroinflammation. Here, we report a case of new-onset schizophrenia in a 16-year-old boy after COVID-19. After developing COVID-19, he entered a catatonic state 4 days later and was hospitalized. Benzodiazepines alleviated his catatonia, but hallucinations and delusions persisted. Encephalitis and epilepsy were excluded by magnetic resonance imaging (MRI), encephalography, and cerebrospinal fluid examination. Psychosis persisted after the virus titer declined and the inflammatory response subsided. Moreover, the patient exhibited delusions of control-a Schneider's first-rank symptom. Schizophrenia was diagnosed, and olanzapine improved his symptoms. He had a brief history of insomnia before COVID-19 but his symptoms did not satisfy the ultra-high-risk criteria. However, COVID-19 may have facilitated development of schizophrenia through neuroinflammation and volume reduction in the gray matter of the right medial temporal lobe. This case demonstrates that infectious diseases in adolescents should be carefully managed, to prevent schizophrenia.

Acute NK1 receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers.

The primary brain structures of reward processing are mainly situated in the mid-brain dopamine system. The nucleus accumbens (NAc) receives dopaminergic projections from the ventral tegmental area and works as a key brain region for the positive incentive value of rewards. Because neurokinin-1 (NK1) receptor, the cognate receptor for substance P (SP), is highly expressed in the NAc, we hypothesized that the SP/NK1 receptor system might play a role in positive reward processing in the NAc in humans. Therefore, we conducted a functional MRI (fMRI) study to assess the effects of an NK1 receptor antagonist on human reward processing through a monetary incentive delay task that is known to elicit robust activation in the NAc especially during gain anticipation. Eighteen healthy adults participated in two series of an fMRI study, taking either a placebo or the NK1 receptor antagonist aprepitant. Behavioural measurements revealed that there was no significant difference in reaction time, hit rate, or self-reported effort for incentive cues between the placebo and aprepitant treatments. fMRI showed significant decrease in blood oxygenation-level-dependent signals in the NAc during gain anticipation with the aprepitant treatment compared to the placebo treatment. These results suggest that SP/NK1 receptor system is involved in processing of positive incentive anticipation and plays a role in accentuating positive valence in association with the primary dopaminergic pathways in the reward circuit.

Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2).

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.