Publications by authors named "Yoshiro Okubo"

182 Publications

Perturbation-Based Balance Training Using Repeated Trips on a Walkway vs. Belt Accelerations on a Treadmill: A Cross-Over Randomised Controlled Trial in Community-Dwelling Older Adults.

Front Sports Act Living 2021 20;3:702320. Epub 2021 Aug 20.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, NSW, Australia.

Walkway and treadmill induced trips have contrasting advantages, for instance walkway trips have high-ecological validity whereas belt accelerations on a treadmill have high-clinical feasibility for perturbation-based balance training (PBT). This study aimed to (i) compare adaptations to repeated overground trips with repeated treadmill belt accelerations in older adults and (ii) determine if adaptations to repeated treadmill belt accelerations can transfer to an actual trip on the walkway. Thirty-eight healthy community-dwelling older adults underwent one session each of walkway and treadmill PBT in a randomised crossover design on a single day. For both conditions, 11 trips were induced to either leg in pseudo-random locations interspersed with 20 normal walking trials. Dynamic balance (e.g., margin of stability) and gait (e.g., step length) parameters from 3D motion capture were used to examine adaptations in the walkway and treadmill PBT and transfer of adaptation from treadmill PBT to a walkway trip. No changes were observed in normal (no-trip) gait parameters in both training conditions, except for a small (0.9 cm) increase in minimum toe elevation during walkway walks ( < 0.01). An increase in the margin of stability and recovery step length was observed during walkway PBT ( < 0.05). During treadmill PBT, an increased MoS, step length and decreased trunk sway range were observed ( < 0.05). These adaptations to treadmill PBT did not transfer to a walkway trip. This study demonstrated that older adults could learn to improve dynamic stability by repeated exposure to walkway trips as well as treadmill belt accelerations. However, the adaptations to treadmill belt accelerations did not transfer to an actual trip. To enhance the utility of treadmill PBT for overground trip recovery performance, further development of treadmill PBT protocols is recommended to improve ecological authenticity.
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http://dx.doi.org/10.3389/fspor.2021.702320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417700PMC
August 2021

A positron emission tomography study of the serotonin1B receptor effect of electroconvulsive therapy for severe major depressive episodes.

J Affect Disord 2021 Nov 17;294:645-651. Epub 2021 Jul 17.

Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.

Background: Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT) receptor is a potential target for treatment of depression and low 5-HT receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression.

Methods: The objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT receptor selective radioligand [C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT receptor binding in depression and a dorsal brain stem region were selected.

Results: Thirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions. In an exploratory analysis, strong correlations between changes in 5-HT receptor binding and agitation scores on the Hamilton Depression Rating Scale after ECT were observed.

Limitations: Albeit representative of a PET study, the sample size is still small and there are potential confounding effects of medication.

Conclusions: Increased 5-HT receptor binding was observed following ECT for depression, corresponding to previous findings of increased 5-HT receptor binding in hippocampus after rapid acting ketamine for treatment resistant depression.
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http://dx.doi.org/10.1016/j.jad.2021.07.060DOI Listing
November 2021

Rapid Inhibition Accuracy and Leg Strength Are Required for Community-Dwelling Older People to Recover Balance From Induced Trips and Slips: An Experimental Prospective Study.

J Geriatr Phys Ther 2021 Jul 26. Epub 2021 Jul 26.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, New South Wales, Australia. UNSW Medicine, Sydney, New South Wales, Australia. Department of Human Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor.

Background And Purpose: Falls can result in bone fractures and disability, presenting a serious threat to quality of life and independence in older adults. The majority of falls in community-living older adults occur while walking and are often caused by trips and slips. The study aimed to identify the specific sensorimotor and psychological factors required for older adults to recover balance from trips and slips.

Methods: Forty-one older adults aged 65 to 87 years were assessed on sensorimotor (knee extension strength, proprioception, postural sway, and edge contrast sensitivity), reaction (simple reaction time, stepping, and catching reaction inhibition), and psychological (general anxiety and concern about falling) measures. Using a harness system, participants walked at 90% of their usual pace on a 10-m walkway that could induce trips and slips in concealed and changeable locations. Post-perturbation responses resulting in more than 30% of body weight being recorded by the harness system were defined as falls. Poisson regressions were used to test associations between the sensorimotor, reaction, and psychological measures and number of falls.

Results: Fifty-one falls occurred in 25 of 41 participants. Poisson regression revealed body mass index, lower-limb proprioception, knee extension strength, rapid inhibition accuracy, concern about falling, and anxiety were significantly associated with the rate of falls. Other measures including postural sway were not statistically significant. Using stepwise Poisson regression analyses, normalized knee extension strength (rate ratio [RR]: 0.68, 95% confidence interval [CI]: 0.47-0.98), and rapid inhibition accuracy (RR: 0.64, 95% CI: 0.46-0.87) were independently associated with falls.

Conclusion: Our findings suggest rapid inhibition accuracy and adequate leg strength are required for older adults to recover balance from trips and slips. The mechanisms for balance recovery during daily life activities are likely different from those for static balance, suggesting the need for task-specific assessments and interventions for fall prevention in older adults.
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http://dx.doi.org/10.1519/JPT.0000000000000312DOI Listing
July 2021

Multi-Atlas MRI-Based Striatum Segmentation for I-FP-CIT SPECT (DAT-SPECT) Compared With the Bolt Method and SPECT-Atlas-Based Segmentation Method Toward the Accurate Diagnosis of Parkinson's Disease/Syndrome.

Front Med (Lausanne) 2021 25;8:662233. Epub 2021 May 25.

Department of Radiology, Nippon Medical School Hospital, Tokyo, Japan.

This study aimed to analyze the performance of multi-atlas MRI-based parcellation for I-FP-CIT SPECT (DAT-SPECT) in healthy volunteers. The proposed method was compared with the SPECT-atlas-based and Bolt methods. F-FE-PE2I-PET (DAT-PET) was used as a reference. Thirty healthy subjects underwent DAT-SPECT, DAT-PET, and 3D-T1WI-MRI. We calculated the striatum uptake ratio (SUR/SBR), caudate uptake ratio (CUR), and putamen uptake ratio (PUR) for DAT-SPECT using the multi-atlas MRI-based method, SPECT-atlas-based method, and Bolt method. In the multi-atlas MRI-based method, the cerebellum, occipital cortex, and whole-brain were used as reference regions. The correlation of age with DAT-SPECT activity and the correlations of SUR/SBR, CUR, and PUR between DAT-SPECT and DAT-PET were calculated by each of the three methods. The correlation between age and SUR/SBR for DAT-SPECT based on the multi-atlas MRI-based method was comparable to that based on the SPECT-atlas-based method ( = -0.441 to -0.496 vs. -0.488). The highest correlation between DAT-SPECT and DAT-PET was observed using the multi-atlas MRI-based method with the occipital lobe defined as the reference region compared with the SPECT-atlas-based and Bolt methods (SUR, CUR, and PUR: 0.687, 0.723, and 0.676 vs. 0.698, 0.660, and 0.616 vs. 0.655). Multi-atlas MRI-based parcellation with the occipital lobe defined as the reference region was at least comparable to the clinical methods.
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http://dx.doi.org/10.3389/fmed.2021.662233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185065PMC
May 2021

Predictors of development and persistence of musculoskeletal pain in community-dwelling older people: A two-year longitudinal study.

Geriatr Gerontol Int 2021 Jun 23;21(6):519-524. Epub 2021 Apr 23.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, New South Wales, Australia.

Aim: The aim of this prospective cohort study was to identify the predictors of the development and persistence of musculoskeletal pain (MSKP) in older people.

Methods: Participants comprised 431 community-dwelling older people aged 70+ years. Demographic, anthropometric, balance, mobility, cognitive function, psychological status and physical activity level measures were obtained at baseline. Participants were asked about the presence of MSKP in the neck/back, hip, knee/leg and/or feet at baseline and two-year follow-up. Logistic regression analyses were performed to identify predictors of the development and persistence of MSKP at two-year follow-up.

Results: Of 179 participants who reported no MSKP at baseline, 84 (46.9%) reported MSKP at two-year follow-up, which was associated with a higher body mass index (odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.18), more reported depressive symptoms (OR 1.30, 95% CI 1.05-1.61) and lower physical activity levels (OR 0.92, 95% CI 0.84-1.00) at baseline. Of 252 participants who reported MSKP at baseline, 202 (80.2%) reported MSKP at follow-up, which was associated with a slower 6-m walking time (OR 1.27, 95% CI 1.08-1.49) and more reported depressive symptoms (OR 1.39, 95% CI 1.09-1.78). These associations remained significant after adjusting for age, sex, comorbidities and medication use.

Conclusions: This study suggests that higher body mass index, more depressive symptoms and less physical activity are predictors of developing MSKP, whereas slow gait speed and depressive symptoms are predictors of the persistence of MSKP among older people. The results highlight the importance of weight control, strategies to improve mental wellbeing and an active lifestyle for pain management among older people. Geriatr Gerontol Int 2021; 21: 519-524.
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http://dx.doi.org/10.1111/ggi.14172DOI Listing
June 2021

Predictors of development and persistence of musculoskeletal pain in community-dwelling older people: A two-year longitudinal study.

Geriatr Gerontol Int 2021 Jun 23;21(6):519-524. Epub 2021 Apr 23.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, New South Wales, Australia.

Aim: The aim of this prospective cohort study was to identify the predictors of the development and persistence of musculoskeletal pain (MSKP) in older people.

Methods: Participants comprised 431 community-dwelling older people aged 70+ years. Demographic, anthropometric, balance, mobility, cognitive function, psychological status and physical activity level measures were obtained at baseline. Participants were asked about the presence of MSKP in the neck/back, hip, knee/leg and/or feet at baseline and two-year follow-up. Logistic regression analyses were performed to identify predictors of the development and persistence of MSKP at two-year follow-up.

Results: Of 179 participants who reported no MSKP at baseline, 84 (46.9%) reported MSKP at two-year follow-up, which was associated with a higher body mass index (odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.18), more reported depressive symptoms (OR 1.30, 95% CI 1.05-1.61) and lower physical activity levels (OR 0.92, 95% CI 0.84-1.00) at baseline. Of 252 participants who reported MSKP at baseline, 202 (80.2%) reported MSKP at follow-up, which was associated with a slower 6-m walking time (OR 1.27, 95% CI 1.08-1.49) and more reported depressive symptoms (OR 1.39, 95% CI 1.09-1.78). These associations remained significant after adjusting for age, sex, comorbidities and medication use.

Conclusions: This study suggests that higher body mass index, more depressive symptoms and less physical activity are predictors of developing MSKP, whereas slow gait speed and depressive symptoms are predictors of the persistence of MSKP among older people. The results highlight the importance of weight control, strategies to improve mental wellbeing and an active lifestyle for pain management among older people. Geriatr Gerontol Int 2021; 21: 519-524.
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http://dx.doi.org/10.1111/ggi.14172DOI Listing
June 2021

Bupropion increases cerebral activation in auditory affective processing: A randomized controlled fMRI study.

Neurosci Lett 2021 04 13;749:135716. Epub 2021 Feb 13.

Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan. Electronic address:

Introduction: Bupropion is an antidepressant with less possibility to give rise to emotional blunting as side effect, and it also acts on improving negative self-recognition in a depressive state. Previous neuroimaging studies indicated a change in brain function by facial expression as an effect of antidepressants. As well as facial expression, vocal affective processing is essential for accurately recognizing another's feelings, but to our knowledge, no study has investigated whether bupropion affects the cerebral function of recognition of auditory affective processing. In this study, we aimed to investigate the acute effect of bupropion on cerebral response to vocal affective processing.

Methods: Sixteen healthy volunteers (male = 8) participated in this study. With a randomized placebo-controlled within-subject trial, two series of fMRI scans, using either placebo or bupropion (150 mg), were examined. An auditory emotional valence judgement task was performed during fMRI scanning. The acute effects of bupropion on cerebral activation in the emotional circuit and behavioral performance during emotional processing were analyzed.

Results: Compared with placebo, bupropion caused a significantly greater activation of emotional voices in the left insula and right superior temporal gyrus, whereas the amygdala was not activated. By bupropion, a significantly greater activation of the positive emotional circuit was observed at the superior temporal gyrus and middle frontal gyrus. As for behavioral performance, no significant difference was observed between placebo and bupropion.

Conclusions: Our findings suggest that bupropion enhances the cerebral response to affective processing, especially positive emotional vocalizations, indicating a possible mechanism underlying the therapeutic effects for patients with depression.
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http://dx.doi.org/10.1016/j.neulet.2021.135716DOI Listing
April 2021

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

Psychiatry Clin Neurosci 2021 Jun 10;75(6):200-207. Epub 2021 Mar 10.

Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.

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.
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http://dx.doi.org/10.1111/pcn.13208DOI Listing
June 2021

Stepping impairment and falls in older adults: A systematic review and meta-analysis of volitional and reactive step tests.

Ageing Res Rev 2021 03 24;66:101238. Epub 2020 Dec 24.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, Australia; School of Population Health, University of New South Wales, Sydney, Australia.

Objective: To systematically examine stepping performance as a risk factor for falls. More specifically, we examined (i) if step tests can distinguish fallers from non-fallers and (ii) the type of step test (e.g. volitional vs reactive stepping) that is required to distinguish fallers from non-fallers.

Data Source: PubMed, EMBASE, CINAHL, Cochrane Database of Systematic Reviews and reference lists of included articles.

Study Selection: Cross-sectional and cohort studies that assessed the association between at least one step test and falls in older people (age ≥ 60 and/or mean age of 65).

Results: A meta-analysis of 61 studies (n = 9536) showed stepping performance was significantly worse in fallers compared to non-fallers (Cohen'sd 0.56, 95 % CI 0.48 to 0.64, p < 0.001, I 66 %). This was the case for both volitional and reactive step tests. Twenty-three studies (n = 3615) were included in a diagnostic meta-analysis that showed that step tests have moderate sensitivity (0.70, 95 % CI 0.62 to 0.77), specificity (0.68, 95 % CI 0.58 to 0.77) and area under the receiver operating characteristics curve (AUC) (0.75, 95 % CI 0.59 to 0.86) in discriminating fallers from non-fallers.

Conclusions: This large systematic review demonstrated that both volitional and reactive stepping impairments are significant fall risk factors among older adults. Step tests can identify fallers from non-fallers with moderate accuracy.
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http://dx.doi.org/10.1016/j.arr.2020.101238DOI Listing
March 2021

Evaluation of dopamine D receptor occupancy by blonanserin using [C]-(+)-PHNO in schizophrenia patients.

Psychopharmacology (Berl) 2021 May 12;238(5):1343-1350. Epub 2020 Nov 12.

Department of Neuropsychiatry, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.

Rationale: Unlike other antipsychotics, our previous positron emission tomography (PET) study demonstrated that a single dose of blonanserin occupied dopamine D as well as dopamine D receptors in healthy subjects. However, there has been no study concerning the continued use of blonanserin.

Objectives: We examined D and D receptor occupancies in patients with schizophrenia who had been treated with blonanserin.

Methods: Thirteen patients with schizophrenia participated. PET examinations were performed on patients treated with clinical dosage of blonanserin or olanzapine alone. A crossover design was used in which seven patients switched drugs after the first scan, and PET examinations were conducted again. D and D receptor occupancies were evaluated by [C]-(+)-PHNO. We used nondisplaceable binding potential (BP) of 6 healthy subjects which we previously reported as baseline. To consider the effect of upregulation of D receptor by continued use of antipsychotics, D receptor occupancy by blonanserin in seven subjects who completed 2 PET scans were re-analyzed by using BP of olanzapine condition as baseline.

Results: Average occupancy by olanzapine (10.8 ± 6.0 mg/day) was as follows: caudate 32.8 ± 18.3%, putamen 26.3 ± 18.2%, globus pallidus - 33.7 ± 34.9%, substantia nigra - 112.8 ± 90.7%. Average occupancy by blonanserin (12.8 ± 5.6 mg/day) was as follows: caudate 61.0 ± 8.3%, putamen 55.5 ± 9.5%, globus pallidus 48.9 ± 12.4%, substantia nigra 34.0 ± 20.6%. EC was 0.30 ng/mL for D receptor for caudate and putamen (df = 19, p < 0.0001) and 0.70 ng/mL for D receptor for globus pallidus and substantia nigra (df = 19, p < 0.0001). EC for D receptor of blonanserin changed to 0.22 ng/mL (df = 13, p = 0.0041) when we used BP of olanzapine condition as baseline.

Conclusions: Our study confirmed that blonanserin occupied both D and D receptors in patients with schizophrenia.
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http://dx.doi.org/10.1007/s00213-020-05698-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062348PMC
May 2021

People With Parkinson's Disease Exhibit Reduced Cognitive and Motor Cortical Activity When Undertaking Complex Stepping Tasks Requiring Inhibitory Control.

Neurorehabil Neural Repair 2020 12 6;34(12):1088-1098. Epub 2020 Nov 6.

Neuroscience Research Australia, University of New South Wales, New South Wales, Australia.

Background: People with Parkinson's disease (PD) have difficulties generating quick and accurate steps in anticipation of and/or in response to environmental hazards. However, neural mechanisms underlying performance in cognitively demanding stepping tasks are unclear.

Objective: This study compared activation patterns in cognitive and motor cortical regions using functional near-infrared spectroscopy (fNIRS) between people with PD and age-matched healthy older adults (HOA) during stepping tasks.

Methods: Fifty-two people with PD and 95 HOA performed a simple choice stepping reaction time test (CSRT) and 2 cognitively demanding stepping tests (inhibitory CSRT [iCSRT] and Stroop stepping test [SST]) on a computerized step mat. Cortical activation in the dorsolateral prefrontal cortex (DLPFC), Broca's area, supplementary motor area (SMA), and premotor cortex (PMC) were recorded using fNIRS. Stepping performance and cortical activity were contrasted between groups and between the CSRT and the iCSRT and SST.

Results: The PD group performed worse than the HOA in all 3 stepping tests. A consistent pattern of interactions indicated differential hemodynamic responses between the groups. Compared with the CSRT, the PD group exhibited reduced DLPFC activity in the iCSRT and reduced SMA and PMC activity in the SST. The HOA exhibited increased DLPFC, SMA, and PMC activity when performing the SST in comparison with the CSRT task.

Conclusions: In contrast to the HOA, the PD group demonstrated reduced cortical activity in the DLPFC, SMA, and PMC during the more complex stepping tasks requiring inhibitory control. This may reflect subcortical and/or multiple pathway damage with subsequent deficient use of cognitive and motor resources.
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http://dx.doi.org/10.1177/1545968320969943DOI Listing
December 2020

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

Int J Neuropsychopharmacol 2021 Feb;24(2):108-117

Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.

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).
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http://dx.doi.org/10.1093/ijnp/pyaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883894PMC
February 2021

Falls in Community-Dwelling Older Adults with Lower Back or Knee Pain Are Associated with Cognitive and Emotional Factors.

Int J Environ Res Public Health 2020 07 9;17(14). Epub 2020 Jul 9.

Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima 890-8520, Japan.

(1) Background: The present study aimed to examine physical, cognitive and emotional factors affecting falls in community-dwelling older adults with and without pain; (2) Methods: Data from 789 older adults who participated in a community-based health survey were analyzed. Participants completed questionnaires on the presence of pain and previous falls. Muscle weakness (handgrip strength < 26.0 kg for men and < 18.0 kg for women) and low skeletal muscle mass (appendicular skeletal muscle mass index < 7.0 kg/m for men and < 5.7 kg/m for women) were determined. Mild cognitive impairment (MCI) and depressive symptoms were assessed using the National Center for Geriatrics and Gerontology-Functional Assessment Tool and 15-item geriatric depression scale (GDS-15), respectively; (3) Results: In participants with pain, MCI and GDS-15 were associated with previous falls after adjusting for age, sex, education and medication use. In participants without pain, muscle weakness and low skeletal muscle mass were associated with previous falls when adjusting for the above covariates; (4) Conclusions: Falls in participants with pain were associated with cognitive and emotional factors, whereas falls in those without pain were associated with physical factors. Fall prevention interventions for older adults with pain may require tailored strategies to address cognitive and emotional factors.
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http://dx.doi.org/10.3390/ijerph17144960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400355PMC
July 2020

Reactive Balance Adaptability and Retention in People With Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Neurorehabil Neural Repair 2020 08 6;34(8):675-685. Epub 2020 Jun 6.

University of New South Wales, Sydney, New South Wales, Australia.

. To compare reactive balance in people with multiple sclerosis (MS) with healthy controls and to examine the ability of people with MS to adapt their reactive balance and retain training effects. . Electronic databases (PubMed, EMBASE, PsychINFO) and reference lists of included articles from inception to February 25, 2019. . Case-control and intervention studies that assessed reactive balance using mechanical perturbations in people with a confirmed diagnosis of MS. . Meta-analyses of 9 studies (n = 342) showed that people with MS have significantly worse reactive balance than healthy controls (standardized mean difference [SMD] 0.78, 95% CI 0.44-1.11, < .0001, = 47%). Specifically, people with MS have greater center of mass displacements (SMD 0.41, 95% CI 0.05-0.77, = .02, = 9%) and longer response times (MD (ms) 31.45, 95% CI 19.91-42.98, < .0001, = 75%) in response to standing perturbations than healthy controls. Subsequent meta-analyses revealed training comprising repeated exposure to perturbations improved response times ( < .001) and training effects on response times could be retained for 24 hours ( < .001) in people with MS. . Reactive balance assessments can highlight functional impairments related to falls in people with MS, and perturbation training can acutely improve reactive balance control and such improvements can be retained for 24 hours in this population. Systematic review registration number: CRD42019126130.
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http://dx.doi.org/10.1177/1545968320929681DOI Listing
August 2020

Electroconvulsive therapy decreases striatal dopamine transporter binding in patients with depression: A positron emission tomography study with [F]FE-PE2I.

Psychiatry Res Neuroimaging 2020 07 4;301:111086. Epub 2020 May 4.

Department of Neuropsychiatry, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan. Electronic address:

Electroconvulsive therapy (ECT) is an effective treatment for major depression. Previous studies suggested that dopaminergic neurotransmission plays a crucial role in the mechanism of the action of ECT. Since dopamine transporters (DAT) regulate extracellular dopamine concentration, DAT represents an interesting target for the study of the mechanism of action of ECT. Eight inpatients (7 patients with major depressive disorder and 1 patient with bipolar disorder with a DSM-IV diagnosis) received a series of 7-15(11.3±5.2) bilateral ECT sessions.The severity of symptoms was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression-Severity (CGI-S). All patients were examined with [F]FE-PE2I positron emission tomography (PET) at pre-ECT, after the 10 ECT, and at post-ECT. Striatal DAT-binding potential (BP) of all patients was reduced, with an average change ratio of DAT-BP of -13.1±5.6%. In the 2 cases with 15 ECT sessions, the ratio change of DAT-BP after the 15th ECT was larger than that after the 10th ECT. Also, HDRS and CGI-S were reduced. These results indicate that the dopamine nervous system is part of themechanism of action of ECT.
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http://dx.doi.org/10.1016/j.pscychresns.2020.111086DOI Listing
July 2020

Impact of pain on reactive balance and falls in community-dwelling older adults: a prospective cohort study.

Age Ageing 2020 10;49(6):982-988

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, Australia.

Background: pain is associated with increased postural sway and falls in older adults. However, the impact of pain on reactive balance induced by postural perturbations and how this might predispose older adults to falls is not known.

Objective: to investigate whether any pain, back/neck pain and lower limb pain are associated with poor reactive balance and prospective fall outcomes in older adults.

Design: 12-month prospective cohort study.

Setting: community.

Subjects: 242 community-dwelling older adults aged 70+ years.

Methods: participants completed a questionnaire on the presence of pain and underwent force-controlled waist-pull postural perturbations while standing. Force thresholds for stepping, step initiation time, step velocity and step length were quantified. Falls were monitored with monthly falls calendars for 12-months.

Results: participants with lower limb pain had significantly lower force thresholds for stepping. Those with any pain or pain in the back/neck had longer step initiation time, slower step velocity and shorter step length. The three pain measures (any pain, back/neck pain, lower limb pain) were significantly associated with multiple falls when adjusted for age, sex, body mass index, use of polypharmacy, strength and walking speed. In mediation analyses, there was a significant indirect effect of reactive balance for the relationship between back/neck pain and falls with fractures.

Conclusions: older people with pain have impaired reactive balance and an increased risk of falls. Reactive balance partially mediated the association between pain and fall-related fractures. Further research is required to confirm the findings of this study.
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http://dx.doi.org/10.1093/ageing/afaa070DOI Listing
October 2020

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

Psychiatry Clin Neurosci 2020 Aug 26;74(8):424-430. Epub 2020 May 26.

Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.

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 [ 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 [ F]FE-PE2I.

Methods: Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [ F]FE-PE2I, which has high affinity and selectivity for DAT. Binding potentials (BP ) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BP values were compared between MDD patients and healthy controls.

Results: MDD patients showed significantly lower DAT BP in the NAc (P = 0.009), and there was a trend of lower BP 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.
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http://dx.doi.org/10.1111/pcn.13020DOI Listing
August 2020

Pain Is Associated With Poor Balance in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.

J Am Med Dir Assoc 2020 05;21(5):597-603.e8

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.

Objectives: Pain is a risk factor for falls in older adults, but the mechanisms are not well understood, limiting our ability to implement effective preventive strategies. The aim of this study was to systematically review and synthesize the literature that has examined the impact of pain on static, dynamic, multicomponent, and reactive balance in community-dwelling older adults.

Design: Systematic review and meta-analysis.

Setting And Participants: Studies from inception to March 2019 were identified from electronic databases (MEDLINE, EMBASE, PsycINFO, CINAHL), contact with the primary authors, and reference lists of included articles.

Methods: Cross-sectional and case-control studies that compared objective balance measures between older (minimum age 60 years) adults with and without pain were included.

Results: Thirty-nine eligible studies (n = 17,626) were identified. All balance modalities (static, dynamic, multicomponent, and reactive) were significantly poorer in participants with pain compared to those without pain. Subgroup analyses revealed that chronic pain (pain persisting ≥3 months) impaired balance more than pain of unspecified duration. The effects of pain at specific sites (neck, lower back, hip, knee, and foot) on balance were not significantly different.

Conclusions And Implications: Pain is associated with poor static, dynamic, multicomponent, and reactive balance in community-dwelling older adults. Pain in the neck, lower back, hip, knee, and foot all contribute to poor balance, and this is even more pronounced for chronic pain. Comprehensive balance and pain characteristic assessments may reveal mechanisms underlying the contribution of pain to instability and increased fall risk in older people.
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http://dx.doi.org/10.1016/j.jamda.2020.02.011DOI Listing
May 2020

Chronic pain is independently associated with social frailty in community-dwelling older adults.

Geriatr Gerontol Int 2019 Nov 23;19(11):1153-1156. Epub 2019 Oct 23.

Department of Physical Therapy Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Aim: The present study aimed to determine whether measures of chronic pain are associated with social frailty in community-dwelling older adults.

Methods: Participants comprised 248 older adults who enrolled for community-based exercise classes. Chronic pain was defined as the presence of significant pain-related symptoms within the past month that had continued for at least 6 months. Social frailty was defined as positive responses to two of the following five questions (going out less frequently, rarely visiting friends, feeling unhelpful to friends or family, living alone and not talking with someone every day). Physical function was assessed using the Chair Stand and Timed Up and Go tests.

Results: A total of 55 participants (22.2%) met the criteria for social frailty. A total of 28 socially frail participants (50.9%) and 56 of the socially integrated participants (29.0%) reported chronic pain. The presence of chronic pain was significantly associated with social frailty after adjusting for age, sex and physical function measures (odds ratio 2.13, 95% confidence interval 1.01-4.48). Chronic pain was also significantly associated with three social frailty items: going out less frequently, rarely visiting friends and feeling unhelpful to friends or family.

Conclusions: Chronic pain was independently associated with social frailty in community-dwelling older adults. Simple assessments of chronic pain and subsequent pain management interventions might be beneficial for older people with social frailty. Geriatr Gerontol Int 2019; 19: 1153-1156.
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http://dx.doi.org/10.1111/ggi.13785DOI Listing
November 2019

Bupropion increases activation in nucleus accumbens during anticipation of monetary reward.

Psychopharmacology (Berl) 2019 Dec 24;236(12):3655-3665. Epub 2019 Jul 24.

Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.

Rationale: Bupropion is used for major depressive disorder, smoking cessation aid, and obesity. It blocks reuptake of dopamine and noradrenaline and antagonizes nicotinic acetylcholine receptor. Animal studies showed that bupropion enhanced rewarding effects. In addition, bupropion has the potential to treat patients with reward processing dysfunction. However, neural substrates underlying the bupropion effects on reward function in human subjects are not fully understood.

Objectives: We investigated single-dose administration of bupropion on neural response of reward anticipation in healthy subjects using a monetary incentive delay (MID) task by functional magnetic resonance imaging (fMRI), especially focusing on nucleus accumbens (NAc) activity to non-drug reward stimuli under bupropion treatment.

Methods: We used a randomized placebo-controlled within-subject crossover design. Fifteen healthy adults participated in two series of an fMRI study, taking either placebo or bupropion. The participants performed the MID task during the fMRI scanning. The effects of bupropion on behavioral performance and blood oxygenation level-dependent (BOLD) signal in NAc during anticipation of monetary gain were analyzed.

Results: We found that bupropion significantly increased BOLD responses in NAc during monetary reward anticipation. The increased BOLD responses in NAc were observed with both low and high reward incentive cues. There was no significant difference between placebo and bupropion in behavioral performance.

Conclusions: Our findings provide support for the notion that bupropion enhances non-drug rewarding effects, suggesting a possible mechanism underlying therapeutic effects for patients with motivational deficit.
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http://dx.doi.org/10.1007/s00213-019-05337-6DOI Listing
December 2019

Differences in the perception of dental sounds: a preliminary study.

Patient Prefer Adherence 2019 3;13:1051-1056. Epub 2019 Jul 3.

Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.

Purpose: The sound of dental treatments can evoke anxiety in some dental patients. While women have shown greater dental anxiety than men, little is known about the gender differences in the perception of dental sounds. The purpose of this preliminary study was to evaluate differences in the perception of dental sounds according to the level of dental fear and gender.

Patients And Methods: Based on the level of dental fear, 69 adults (39 women, 30 men; average age, 28.1±8.1 years) were categorized into four groups. Three types of sounds were presented to participants: two sounds associated with dental treatment and a neutral sound. All participants rated their emotional reaction to each sound on a visual analog scale.

Results: Significant differences were observed for ratings of valence and disgust for a dental drilling sound among the four groups (=0.007 and 0.004, respectively). Female participants in the dental fear group rated the dental drilling sound as more negative and disgusting than did female participants in the control group (=0.002 for both ratings). However, no significant differences were found in ratings between males in the dental fear and control groups.

Conclusion: Perception of dental sounds appears to differ by level of dental fear and by gender. Considering these differences may contribute to reducing fear in dental patients.
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http://dx.doi.org/10.2147/PPA.S204465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614825PMC
July 2019

A pilot study of reactive balance training using trips and slips with increasing unpredictability in young and older adults: Biomechanical mechanisms, falls and clinical feasibility.

Clin Biomech (Bristol, Avon) 2019 07 10;67:171-179. Epub 2019 May 10.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, NSW, Australia; The Japan Society for the Promotion of Science, Tokyo, Japan.

Background: Exposure to unpredictable trips and slips can improve balance recovery responses but it was not known if older adults can tolerate such high intensity training. The study aim was to determine if reactive balance in both young and older adults could be trained in a single day through exposure to slip and trip hazards hidden in unpredictable walkway locations.

Methods: Ten young (20-40 yr) and ten older adults (65 + yr) completed 32 trials on a 10-meter trip and slip walkway; 14 slip trials, 14 trip trials and 4 no-perturbation trials presented in a pseudo-random order. Participant usual gait speed was regulated using a metronome and stepping tiles at fixed distances. Gait kinematics (Vicon motion capture), falls (> 30% body weight into the harness), anxiety and confidence to avoid falling were assessed.

Findings: Margin of stability for balance recovery after slips substantially improved at training completion for older adults (effect size = 1.13, P = 0.019). Falls from slips also decreased: 44.4% to 0% in the young adults; and 28.6% to 14.3% in the older adults. Although confidence to avoid falling did not change, anxiety increased during training with one young and three older participants withdrawing during training.

Interpretations: The findings indicate exposure to unpredictable perturbations improves reactive balance in young and older adults. However, improvements of balance recovery from trips were not significant. Elevated anxiety levels and a high dropout rate suggest the need for more individualised training over multiple days.
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http://dx.doi.org/10.1016/j.clinbiomech.2019.05.016DOI Listing
July 2019

Acute Atomoxetine Selectively Modulates Encoding of Reward Value in Ventral Medial Prefrontal Cortex.

J Nippon Med Sch 2019 ;86(2):98-107

Department of Pharmacology, Graduate School of Medicine, Nippon Medical School.

Background: A recent neurocognitive model of attention-deficit hyperactivity disorder (ADHD) has proposed a primary deficit in reward function as well as in executive function to account for underlying neural substrates of ADHD symptoms. Atomoxetine has been widely used as a non-stimulant medication for ADHD with little abuse liability. Although animal studies have reported that atomoxetine increases extracellular levels of both noradrenaline and dopamine in the prefrontal cortex, which receives input from a mesocorticolimbic pathway involved in reward function, there have been few studies in humans concerning the effects of atomoxetine in terms of reward function. Therefore, we investigated whether a single dose of atomoxetine (acute atomoxetine) affects reward processing in healthy adults.

Methods: We used functional magnetic resonance imaging and adopted the monetary incentive delay task to separately examine neural responses to monetary reward anticipation in the nucleus accumbens and outcome in the ventral medial prefrontal cortex (vmPFC). The experiment was designed as a randomized, placebo-controlled within-subjects cross-over trial. Fourteen healthy adults completed two series of studies, taking either atomoxetine or placebo.

Results: Atomoxetine significantly decreased vmPFC activation during gain outcome compared to placebo. In gain anticipation, however, atomoxetine did not show a significant increase in the nucleus accumbens activation compared with placebo.

Conclusions: These results suggest that atomoxetine affects reward value encoding through selective modulation of vmPFC activity related to reward outcome. Therefore, such modulatory action may partly contribute to a therapeutic effect of atomoxetine for a group of ADHD patients with increased activity in vmPFC.
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http://dx.doi.org/10.1272/jnms.JNMS.2019_86-205DOI Listing
November 2019

Effect of Reactive Balance Training Involving Repeated Slips and Trips on Balance Recovery Among Older Adults: A Blinded Randomized Controlled Trial.

J Gerontol A Biol Sci Med Sci 2019 08;74(9):1489-1496

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, New South Wales, Australia.

Background: This study examined whether reactive balance training (exposures to slips and trips) could improve balance recovery and reduce perturbation-induced falls among older adults.

Methods: Forty-four community-dwelling older adults participated in a parallel, blinded randomized controlled trial conducted in a research institute in Sydney, Australia in 2017-2018 (ACTRN12617000564358). The intervention group (n = 22) underwent three 40 minutes sessions (total 120 minutes) that exposed them to (1) 20 trips, (2) 20 slips, and (3) 10 trips and 10 slips in mixed order, over 2 days. The control group (n = 22) received one 40 minutes session of sham training. The primary outcome was falls (>30% body weight in harness) when exposed to trips and slips at post-assessment.

Results: At post-assessment, a total of 51 falls (23 and 27 falls from induced slips and trips, respectively) were recorded in the laboratory. Relative to the control group, the intervention group experienced fewer total falls (rate ratio [RR] = 0.40, 95% confidence interval [CI] = 0.22-0.76), slip falls (RR = 0.33, 95% CI = 0.12-0.90) and trip falls (RR = 0.49, 95% CI = 0.21-1.12). Eight participants reported adverse events (5 in the intervention group and 3 in the control group) which were related mainly to discomfort caused by a suboptimal harness used in the initial stages of the trial.

Conclusions: The reactive balance training reduced perturbation-induced falls by 60% indicating improved balance recovery from trips and slips. A comfortable safety harness system is essential to prevent discomfort. Reactive balance training may complement traditional exercise programs in fall prevention interventions.
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http://dx.doi.org/10.1093/gerona/glz021DOI Listing
August 2019

Effect of Reactive Balance Training Involving Repeated Slips and Trips on Balance Recovery Among Older Adults: A Blinded Randomized Controlled Trial.

J Gerontol A Biol Sci Med Sci 2019 08;74(9):1489-1496

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, New South Wales, Australia.

Background: This study examined whether reactive balance training (exposures to slips and trips) could improve balance recovery and reduce perturbation-induced falls among older adults.

Methods: Forty-four community-dwelling older adults participated in a parallel, blinded randomized controlled trial conducted in a research institute in Sydney, Australia in 2017-2018 (ACTRN12617000564358). The intervention group (n = 22) underwent three 40 minutes sessions (total 120 minutes) that exposed them to (1) 20 trips, (2) 20 slips, and (3) 10 trips and 10 slips in mixed order, over 2 days. The control group (n = 22) received one 40 minutes session of sham training. The primary outcome was falls (>30% body weight in harness) when exposed to trips and slips at post-assessment.

Results: At post-assessment, a total of 51 falls (23 and 27 falls from induced slips and trips, respectively) were recorded in the laboratory. Relative to the control group, the intervention group experienced fewer total falls (rate ratio [RR] = 0.40, 95% confidence interval [CI] = 0.22-0.76), slip falls (RR = 0.33, 95% CI = 0.12-0.90) and trip falls (RR = 0.49, 95% CI = 0.21-1.12). Eight participants reported adverse events (5 in the intervention group and 3 in the control group) which were related mainly to discomfort caused by a suboptimal harness used in the initial stages of the trial.

Conclusions: The reactive balance training reduced perturbation-induced falls by 60% indicating improved balance recovery from trips and slips. A comfortable safety harness system is essential to prevent discomfort. Reactive balance training may complement traditional exercise programs in fall prevention interventions.
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http://dx.doi.org/10.1093/gerona/glz021DOI Listing
August 2019

Exposure to trips and slips with increasing unpredictability while walking can improve balance recovery responses with minimum predictive gait alterations.

PLoS One 2018 18;13(9):e0202913. Epub 2018 Sep 18.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Sydney, New South Wales, Australia.

Introduction: The primary study aim was to determine if repeated exposure to trips and slips with increasing unpredictability while walking can improve balance recovery responses when predictive gait alterations (e.g. slowing down) are minimised. The secondary aim was to determine if predictive gait alterations acquired through exposure to perturbations at a fixed condition would transfer to highly unpredictable conditions.

Methods: Ten young adults were instructed to step on stepping tiles adjusted to their usual step length and to a metronome adjusted to their usual cadence on a 10-m walkway. Participants were exposed to a total of 12 slips, 12 trips and 6 non-perturbed trials in three conditions: 1) right leg fixed location, 2) left leg fixed location and 3) random leg and location. Kinematics during non-perturbed trials and pre- and post-perturbation steps were analysed.

Results: Throughout the three conditions, participants walked with similar gait speed, step length and cadence(p>0.05). Participants' extrapolated centre of mass (XCoM) was anteriorly shifted immediately before slips at the fixed location (p<0.01), but this predictive gait alteration did not transfer to random perturbation locations. Improved balance recovery from trips in the random location was indicated by increased margin of stability and step length during recovery steps (p<0.05). Changes in balance recovery from slips in the random location was shown by reduced backward XCoM displacement and reduced slip speed during recovery steps (p<0.05).

Conclusions: Even in the absence of most predictive gait alterations, balance recovery responses to trips and slips were improved through exposure to repeated unpredictable perturbations. A common predictive gait alteration to lean forward immediately before a slip was not useful when the perturbation location was unpredictable. Training balance recovery with unpredictable perturbations may be beneficial to fall avoidance in everyday life.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202913PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143193PMC
February 2019

Acute tramadol enhances brain activity associated with reward anticipation in the nucleus accumbens.

Psychopharmacology (Berl) 2018 Sep 27;235(9):2631-2642. Epub 2018 Jun 27.

Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan.

Background: Tramadol is an analgesic with monoamine reuptake inhibition and μ-opioid receptor activation. Although tramadol has been widely used for treatment of various pain conditions, there is controversy over the risk of abuse potential. We examined the effects of tramadol on the reward system in humans using functional magnetic resonance imaging (fMRI) to assess the potential of tramadol for drug abuse or dependence.

Methods: A randomized, double-blind, placebo-controlled, crossover study was conducted for 19 healthy adults under tramadol or placebo. In association with subjective mood questionnaires, monetary incentive delay (MID) task was performed to assess the neural response to reward anticipation during fMRI. Subjective mood measures and blood oxygenation level-dependent (BOLD) signal during gain and loss anticipation were compared between tramadol and placebo.

Results: Tramadol significantly reduced anxiety (Z = - 2.513, p = 0.012) and enhanced vigor (Z = - 2.725, p = 0.006) compared with placebo. By Mood Rating Scale, tramadol provoked contented (Z = - 2.316, p = 0.021), relaxed (Z = - 2.236, p = 0.025), and amicable feelings (Z = - 2.015, p = 0.044) as well as increased alertness (Z = - 1.972, p = 0.049) and contentedness domains (Z = - 2.174, p = 0.030) compared with placebo. Several brain regions including nucleus accumbens (NAc) were activated during gain anticipation in the MID task under both tramadol and placebo. Tramadol increased the %BOLD signal change in NAc at +¥500 cue significantly more than the placebo (Z = - 2.295, p = 0.022).

Conclusion: Tramadol enhances the reward system and thereby may have abuse potential or precipitate drug abuse in human.
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http://dx.doi.org/10.1007/s00213-018-4955-zDOI Listing
September 2018

The 5-HT receptor - a potential target for antidepressant treatment.

Psychopharmacology (Berl) 2018 05 15;235(5):1317-1334. Epub 2018 Mar 15.

Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Centrum för psykiatriforskning, R5:0, Karolinska Universitetssjukhuset i Solna, -171 76, Stockholm, SE, Sweden.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The serotonin hypothesis may be the model of MDD pathophysiology with the most support. The majority of antidepressants enhance synaptic serotonin levels quickly, while it usually takes weeks to discern MDD treatment effect. It has been hypothesized that the time lag between serotonin increase and reduction of MDD symptoms is due to downregulation of inhibitory receptors such as the serotonin 1B receptor (5-HT1BR). The research on 5-HT1BR has previously been hampered by a lack of selective ligands for the receptor. The last extensive review of 5-HT1BR in the pathophysiology of depression was published 2009, and based mainly on findings from animal studies. Since then, selective radioligands for in vivo quantification of brain 5-HT1BR binding with positron emission tomography has been developed, providing new knowledge on the role of 5-HT1BR in MDD and its treatment. The main focus of this review is the role of 5-HT1BR in relation to MDD and its treatment, although studies of 5-HT1BR in obsessive-compulsive disorder, alcohol dependence, and cocaine dependence are also reviewed. The evidence outlined range from animal models of disease, effects of 5-HT1B receptor agonists and antagonists, case-control studies of 5-HT1B receptor binding postmortem and in vivo, with positron emission tomography, to clinical studies of 5-HT1B receptor effects of established treatments for MDD. Low 5-HT1BR binding in limbic regions has been found in MDD patients. When 5-HT1BR ligands are administered to animals, 5-HT1BR agonists most consistently display antidepressant-like properties, though it is not yet clear how 5-HT1BR is best approached for optimal MDD treatment.
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http://dx.doi.org/10.1007/s00213-018-4872-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919989PMC
May 2018

Hypofunction of left dorsolateral prefrontal cortex in depression during verbal fluency task: A multi-channel near-infrared spectroscopy study.

J Affect Disord 2018 04 2;231:83-90. Epub 2018 Feb 2.

Department of Mental Health, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan.

Background: Previous functional neuroimaging studies of depression have demonstrated frontotemporal dysfunction, including the dorsolateral prefrontal cortex, while patients perform working memory and language comprehension tasks. Recent near-infrared spectroscopy (NIRS) studies have shown frontotemporal hypofunction in depression by verbal fluency task, but the regions of impairment affecting respective depressive symptoms still remain unclear. We investigated frontotemporal function during word production task in depression with multi-channel NIRS. Further, we aimed to clarify whether any depressive symptoms affect frontotemporal dysfunction.

Methods: One hundred seventy-seven major depressive patients and 50 healthy control volunteers participated in this study. Their cerebral activations were compared during verbal fluency task.

Results: Although performance was not significantly different, hypoactivation in the bilateral frontotemporal regions was significantly observed in depressed patients, compared with controls. Left lateral frontotemporal activation was significantly reduced in the group with mandatory symptom, which is depressed mood, or loss of interest or pleasure, compared with the group that still has residual depressive symptoms in spite MDD having been remitted.

Limitation: the MDD group had significantly higher age and education level than the controls. Conclusions Our findings indicate hypofunction of the bilateral frontotemporal regions in depression during verbal fluency task. Further, hypofunction of these regions in the left hemisphere by this task could reflect whether the subjects recovered from depressed mood, or loss of interest or pleasure.
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http://dx.doi.org/10.1016/j.jad.2018.01.010DOI Listing
April 2018
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