Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group.

The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity.

The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

Exploring Hemodynamic Responses Using Mirror Visual Feedback With Electromyogram-Triggered Stimulation and Functional Near-Infrared Spectroscopy.

In recent years, mirror visual feedback (MVF) therapy combined with electrical stimulation (ES) have been proposed for patients with hemiparesis. However, the neurophysiological effect remains unknown. We investigated the effects of MVF by itself and along with electromyogram-triggered ES (ETES) on hemodynamic responses using functional near-infrared spectroscopy (NIRS). Eighteen healthy subjects participated in this study. We measured changes in brain oxygenation using 48 NIRS channels. We investigated the effects of three main factors of visual feedback (observation of a mark, right hand, and hand movements via mirror) with or without ES on bilateral precentral gyrus (PrG), postcentral gyrus (PoG), supplementary motor area (SMA), supramarginal gyrus area (SMG), and angular gyrus (AG) to determine the contribution of each factor. The results showed that the left PoG was significantly more activated when performing mirrored tasks (MT) than when performing circle or Right-hand Tasks (RTs). In addition, the right PoG and right SMA in MT were significantly more activated than in MT + ES cases. Our findings suggested that observation of movements through the mirror caused activation of the postcentral gyrus rather than the PrG, and MVF along with ETES decreased cortical activation.

Cycling Wheelchair Provides Enjoyable Pedaling Exercises with Increased Physiological Indexes.

The cycling wheelchair (CWC) can be used as a pedaling exercise machine. However, physiological indexes in the CWC at various pedaling rates and the difference between the CWC and the existing pedaling machines such as the portable ergometer (ERG) are unclear. The aim of this study was to measure physiological indexes in the CWC at various pedaling rates and compare the CWC to the ERG, focusing on psychological stress. The present non-randomized crossover study included ten healthy men (22.3 ± 1.2 years) who performed pedaling exercise with the CWC and the ERG. Both experiments were composed of three pedaling exercise sessions (40, 60, and 80 rpm). Physiological indexes, consisting of oxygen consumption, heart rate, perceived breathlessness and leg fatigue, and salivary amylase activity (SAA), an index of psychological stress, were measured. The metabolic equivalent (METs) and the rate of change in SAA from rest to immediately after each pedaling session (ΔSAA) were calculated. In the CWC, all physiological indexes significantly increased with pedaling rates. The METs were 2.2 ± 0.3, 2.7 ± 0.4, and 3.5 ± 0.4 at 40, 60, and 80 rpm, respectively. In comparison between the CWC and the ERG, ΔSAA was lower in the CWC than in the ERG at 60 and 80 rpm. Our results indicate that the CWC pedaling can provide low or moderate intensity exercises with adjusting pedaling rates and is less stressful than the ERG. Thus, the CWC is a useful pedaling machine to promote regular and enjoyable exercises.

Stereo-controlled synthesis of polyheterocycles via the diene-transmissive hetero-Diels-Alder reaction of ß,γ-unsaturated α-keto esters.

We describe the stereoselective synthesis of polyring-fused heterocyclic compounds based on diene-transmissive hetero-Diels-Alder reactions utilizing ß,γ-unsaturated α-keto esters. This protocol involves the initial endo- or exo-selective Diels-Alder (DA) reactions with electron-rich dienophiles, methylenation of the ester carbonyl groups with the Tebbe reagent, and a stereoselective second DA reaction with electron-deficient dienophiles. The use of enantioselective DA reactions in the initial reaction enables access to chiral polyring-fused heterocyclic compounds with multiple chiral centres.

Evaluation of motor performances of hemiplegic patients using a virtual cycling wheelchair: an exploratory trial.

Cycling is known to be an effective rehabilitation exercise for hemiplegic patients who face difficulty during walking because of stroke or other brain disorders. A cycling wheelchair (CWC) is a useful tool to provide exercise for these patients and improve their quality of life. In previous studies, our group developed a system that allows patients to safely practice driving a CWC in a virtual environment. However, it has been difficult to check their motor performances and determine the effects of the exercise on a daily basis. This study is an exploratory trial for developing a method to evaluate the motor performances of users based on their CWC pedaling patterns. An experiment with some hemiplegic patients and healthy subjects was conducted and their pedaling patterns were analyzed. Results showed a significant difference between the hemiplegic patients and healthy subjects in an index that reflects pedaling balance between the feet. This result indicates a possible method of evaluating the motor performances of users based on their pedaling patterns.

Electrical stimulation of the abdomen preserves motor performance in the inactive elderly: a randomized controlled trial.

Abdominal muscle strength declines easily with the process of aging and/or disuse, and it is difficult to strengthen weak abdominal muscles in the inactive elderly. In the present study, we applied surface electrical stimulation (ES) to the abdomen of inactive elderly people to investigate its chronic effects. Twenty inactive elderly people (65-89 years) who spent most of the day in their bedroom participated in the study. The subjects were assigned to ES and non-ES groups in a random order. In addition to conventional physical therapy and occupational therapy, ES was applied to both sides of the flank of 10 subjects (ES group) for 8 weeks. For evaluation of the abdominal muscles, the cross-sectional area (CSA) was measured with computed tomography and the electrical muscle activity (iEMG) was measured by electromyography. Functional examinations were performed at 2, 4, and 8 weeks after the beginning of the study with the following parameters: grip strength; maximum walking speed (WS); movement time for sitting up (MSU); number of trunk flexions (NTF); flexibility of the trunk; sit-to-stand time (STS); and Barthel index (BI) score. In the ES group, the NTF and MSU were significantly improved at 4 weeks and thereafter. Furthermore, the STS and WS were also improved significantly after 8 weeks (p < 0.05). The CSA and iEMG both increased significantly (p < 0.05). However, the flexibility of the trunk and BI score did not change. In conclusion, ES to the abdomen has the potential to improve motor function in the inactive elderly.

Functional Changes in the Care-needing Elderly after Surface Electrical Stimulation to the Abdomen.

BACKGROUND: Strength of the trunk muscles is a key component of motor control, but it declines easily with the process of aging and/or disuse. OBJECTIVES: To investigate the effects of surface electrical stimulation (ES) to the abdominal muscles and the motor performance for care-needing elderly. DESIGN: Controlled trial. PARTICIPANTS: Twenty-one elderly people (60-90 years) with care-needing, who were admitted to a nursing home or hospital for daily care and their score of Barthel Index had been stable from 55.3 ± 19.4 to 55.3 ± 19.8 during 3 months before intervention. INTERVENTION: Common physical/occupational therapy was performed for all of the subjects during the study period. ES was applied to the abdomen of 15 subjects (ES group) twice a day for 8 weeks. MEASUREMENTS: Functional measurements were performed before and after beginning of the study with some parameters as follows: grip strength; movement time for sitting up (MSU); maximum walking speed (WS). RESULTS: No significant differences between two groups were noted for characteristics at baseline. In the ES group, MSU (from 21.1 ± 21.4 to 10.4 ± 8.3 sec) significantly improved (p < 0.05) after 8weeks. WS (from 17.7 ± 12.1 to 24.3 ± 15.3 m/min) were also improved (p < 0.05) after 8 weeks. LIMITATIONS: A limitation of this study was the small sample size. CONCLUSIONS: ES to the abdominal area has the potential to improve motor function in the care-needing elderly through reinforcement of the abdominal muscles.

Development of a virtual reality system to evaluate skills needed to drive a cycling wheel-chair.

A cycling wheel chair (CWC) is a useful tool to provide physical exercise for patients who face difficulty walking, caused by stroke or other brain disorders. A system has been developed for rehabilitation, which allows patients to practice driving a CWC in a virtual environment. In this study, hardware improvements were developed and methods for evaluating driving skills were investigated to improve the practical application of this system. The hardware was changed to enable users to drive the CWC they were using in their daily lives. In addition, four types of test scenarios that focused on basic and important actions necessary to drive a CWC, such as pedaling and steering, were developed. An experiment with healthy young and elderly persons was conducted to evaluate the validity of the system. Results showed that pedaling and steering skills were improved in both the young and elderly subjects but the improvement patterns differed between them. These results indicate that repeated practice with the proposed system enhances the safety of driving a CWC, particularly for elderly users.

Fuzzy FES controller using cycle-to-cycle control for repetitive movement training in motor rehabilitation. Experimental tests with wireless system.

A prototype of wireless surface electrical stimulation system combined with the fuzzy FES controller was developed for rehabilitation training with functional electrical stimulation (FES). The developed FES system has three features for rehabilitation training: small-sized electrical stimulator for surface FES, wireless connection between controller and stimulators, and between controller and sensors, and the fuzzy FES controller based on the cycle-to-cycle control for repetitive training. The developed stimulator could generate monophasic or biphasic high voltage stimulus pulse and could output stimulation pulses continuously more than 20 hours with 4 AAA batteries. The developed system was examined with neurologically intact subjects and hemiplegic subjects in knee joint control. The maximum knee joint angle was controlled by regulating burst duration of stimulation pulses by the fuzzy controller. In the results of two experiments of knee extension angle control and knee flexion and extension angle control, the maximum angles reached their targets within small number of cycles and were controlled stably in the stimulation cycles after reaching the target. The fuzzy FES controller based on the cycle-to-cycle control worked effectively to reach the target angle and to compensate difference in muscle properties between subjects. The developed wireless surface FES system would be practical in clinical applications of repetitive execution of similar movements of the limbs for motor rehabilitation with FES.

Increase of muscle activities in hemiplegic lower extremity during driving a cycling wheelchair.

For the patients with severe hemiplegia, long-time wheelchair sitting is unavoidable, which however increases a risk of secondary impairments due to non-use of the affected leg. A cycling wheelchair (C-W/C) has a possibility to activate paretic muscle through self-locomotion with bilateral pedaling. We therefore measured driving speed of C-W/C and electromyogram (EMG) in both legs during driving in the healthy adults and severe hemiplegic patients. Ten healthy volunteers (mean age 32.8, 26-45 years) and ten non-ambulatory post-stroke patients (mean age 69.0, 55-81 years) with complete or semi-complete hemiplegia participated in this study. EMG was recorded from the key muscles for cycling during isometric movement as baseline and during driving a C-W/C straightforward. All of the patients could drive a C-W/C with mean maximum driving speed of 46.6 (31.7-61.7) m/min, which was about half of that in the healthy subjects and within practical level. Root mean square of EMG (R-EMG) as a parameter reflecting muscle activity was compared between baseline and C-W/C driving. There was no increase in most of the values of R-EMG during driving in the healthy subjects and in the intact side of the hemiplegic patients. In contrast, significant increase was found during driving in several paretic muscles, despite that EMG of the paretic leg showed almost silent at baseline. These results suggest C-W/C can induce muscle activities of the paretic leg and provide a chance of practical locomotion even for the severe hemiplegics. Daily use of a C-W/C may contribute to restore paretic leg function.

Modulation of excitability in the cerebral cortex projecting to upper extremity muscles by rotational positioning of the forearm.

The forearm rotation changes sensory inputs to the central nervous system, thereby providing orientation of the hand for grasping an object. Electrical activities of the muscles, induced by transcranial magnetic stimulation to the brain, i.e., motor evoked potentials (MEPs), are used for estimation of the excitability of motor neurons in the brain and spinal cord. It is well known that rotational positioning of the forearm influences MEPs of forearm muscles through modulation of excitability in the central nervous system. In the present study, we investigated whether such a posture-dependent change of MEPs could be found in upper arm and intrinsic hand muscles at three different rotational forearm positions: the most internal (pronation), neutral, and most external (supination) positions of rotation. MEPs were simultaneously recorded from the four muscles, biceps brachii (BB), triceps brachii (TB), abductor digiti minimi (ADM), and abductor pollicis brevis (AbPB). MEP amplitudes and latencies in BB, TB and ADM were significantly larger and shorter, respectively, in supination compared to the values in other positions. By contrast, MEP of AbPB in supination was lower in amplitude and longer in latency. Importantly, muscle lengths of TB, ADM and AbPB are constant in any rotational forearm positions, excluding the possibility of the muscle-length dependent change of spinal reflex. Therefore, these results might be attributable to the posture-dependent modulation of the motor cortex activity for the upper limb. The motor cortex probably changes the control strategy for the upper limb muscles in accordance with the sensory input from the forearm.

Virtual reality pencil and paper tests for neglect: a protocol.

Hemispatial neglect is a common disorder that can occur after a lesion in the right hemisphere. Its main characterization is the difficulty in processing visual stimuli emanating from the space contralateral to the lesion. Pencil and paper tests (such as target cancellation, line bisection, or drawing copy) are used to diagnose neglect. We propose using virtual reality technology and haptic force feedback to enhance pencil and paper tests. Our system can track the patients' eye-gaze and their hand movements. Also, the efficiency of several techniques used to decrease the neglect in different sensory spaces are investigated.

Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation.

The purpose of this study is to examine the morphological and kinematical changes of the uterus induced by electrical stimulation applied to the skin just above the second and fourth posterior sacral foramens (sacral surface electrical stimulation [ssES]) in 26 healthy subjects. Out of them, eight subjects who had severe pain subjectively during every menstruation received ssES just in menstruation. Morphological and functional changes of the uterus were examined by using T2-weighted magnetic resonance (MR) imaging and T1-weighted MR cinematography, respectively. Cyclic electrical stimulation for 15 min with 5 sec ON and 5 sec OFF was applied just before MR scanning. A decrease in thickness of the muscular layer of the uterus was observed in every subject after ssES for 15 min and was significant as compared with the thickness before ssES. Periodic uterine movement during menstruation was observed in the subjects with severe menstrual pain in MR cine and the power spectrum analysis of the movement showed a marked decrease in peak power and frequency after ssES treatment. We conclude that ssES causes a reduction of static muscle tension of the uterus in all menstrual cycle periods and suppression of uterine peristalsis during menstruation in the subjects with severe menstrual pain. Possible neural mechanisms for these static and dynamic effects of ssES on the uterus at spinal level are discussed.

Diagnosis and rehabilitation of hemispatial neglect patients with virtual reality technology.

Victims of a stroke or an accident with damage on the parietal lobe can suffer from hemispatial neglect. This disorder is characterized by misperception of the space contralateral to the damaged area. Paper and pencil tests, such as line bisection tests, are used to diagnose hemispatial neglect. Unfortunately, they fail to quantify the degree of the neglect. Moreover, the neglect has different manifestations in each sensorial space and frame of references. In order to diagnose disorders of spatial recognition and analyze the neglected area in visual and somatic spaces, we developed a 3D-haptic virtual reality system coupled with an eye-tracking device. The haptic interface was used to interact with virtual objects. The virtual world can use the eye-gaze information to let patients overcome the neglect. We tested the system at a rehabilitation center and observed different approaches between normal subjects and hemiplegics patients. The first group was getting close to the target and then slowed down to grab it, whereas the later group proceeded by trial and error. The feature of trajectories of the hand in the 3D space could be used to determine the degree of the motion handicap. However, more specific virtual worlds are needed for efficiently extracting the feature of the patients.

Diagnosis and rehabilitation of patients with hemispatial neglect using virtual reality technology.

Our objective is to develop and test a system for diagnosis and rehabilitation of patients with hemispatial neglect. The system consists of a 3D-haptic virtual world seen through stereo shutter-glasses. Patients interact by manipulating a haptic interface. The software adapts the virtual world accordingly to haptic interface and eye tracking feedback. Offline analysis is possible by reviewing recorded data. Observations made during experimentations with hemiplegics patients and future works with hemispatial neglect patients are discussed.