Corticospinal interface to restore voluntary control of joint torque in a paralyzed forearm following spinal cord injury in non-human primates.

The corticospinal tract plays a major role in the control of voluntary limb movements, and its damage impedes voluntary limb control. We investigated the feasibility of closed-loop brain-controlled subdural spinal stimulation through a corticospinal interface for the modulation of wrist torque in the paralyzed forearm of monkeys with spinal cord injury at C4/C5. Subdural spinal stimulation of the preserved cervical enlargement activated multiple muscles on the paralyzed forearm and wrist torque in the range from flexion to ulnar-flexion. The magnitude of the evoked torque could be modulated by changing current intensity. We then employed the corticospinal interface designed to detect the firing rate of an arbitrarily selected "linked neuron" in the forearm territory of the primary motor cortex (M1) and convert it in real time to activity-contingent electrical stimulation of a spinal site caudal to the lesion. Linked neurons showed task-related activity that modulated the magnitude of the evoked torque and the activation of multiple muscles depending on the required torque. Unlinked neurons, which were independent of spinal stimulation and located in the vicinity of the linked neurons, exhibited task-related or -unrelated activity. Thus, monkeys were able to modulate the wrist torque of the paralyzed forearm by modulating the firing rate of M1 neurons including unlinked and linked neurons via the corticospinal interface. These results suggest that the corticospinal interface can replace the function of the corticospinal tract after spinal cord injury.

Tuning of motor outputs produced by spinal stimulation during voluntary control of torque directions in monkeys.

Spinal stimulation is a promising method to restore motor function after impairment of descending pathways. While paresis, a weakness of voluntary movements driven by surviving descending pathways, can benefit from spinal stimulation, the effects of descending commands on motor outputs produced by spinal stimulation are unclear. Here, we show that descending commands amplify and shape the stimulus-induced muscle responses and torque outputs. During the wrist torque tracking task, spinal stimulation, at a current intensity in the range of balanced excitation and inhibition, over the cervical enlargement facilitated and/or suppressed activities of forelimb muscles. Magnitudes of these effects were dependent on directions of voluntarily produced torque and positively correlated with levels of voluntary muscle activity. Furthermore, the directions of evoked wrist torque corresponded to the directions of voluntarily produced torque. These results suggest that spinal stimulation is beneficial in cases of partial lesion of descending pathways by compensating for reduced descending commands through activation of excitatory and inhibitory synaptic connections to motoneurons.

The ventral striatum contributes to the activity of the motor cortex and motor outputs in monkeys.

The ventral striatum (VSt) is thought to be involved in the vigor of motivated behavior and is suggested to be a limbic-motor interface between limbic areas involved in motivational processes and neural circuits regulating behavioral outputs. However, there is little direct evidence demonstrating the involvement of the VSt in motor control for motivated behaviors. To clarify the functional role of the VSt in motor control, we investigated the effect of reversible pharmacological inactivation of the VSt on the oscillatory activity of the sensorimotor cortices and motor outputs in two macaque monkeys. VSt inactivation reduced movement-related activities of the primary motor cortex and premotor area at 15-120 Hz and increased those at 5-7 Hz. These changes were accompanied by reduced torque outputs but had no effect on the correct performance rate. The present study provides direct evidence that the VSt regulates activities of the motor cortices and motor output.

A multisynaptic pathway from the ventral midbrain toward spinal motoneurons in monkeys.

Motivation boosts motor performance. Activity of the ventral midbrain (VM), consisting of the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) and the retrorubral field (RRF), plays an important role in processing motivation. However, little is known about the neural substrate bridging the VM and the spinal motor output. We hypothesized that the VM might exert a modulatory influence over the descending motor pathways. By retrograde transneuronal labelling with rabies virus, we demonstrated the existence of multisynaptic projections from the VM to the cervical enlargement in monkeys. The distribution pattern of spinal projection neurons in the VM exhibited a caudorostral gradient, in that the RRF and the caudal part of the SNc contained more retrogradely labelled neurons than the VTA and the rostral part of the SNc. Electrical stimulation of the VM induced muscle responses in the contralateral forelimb with a delay of a few milliseconds following the responses of the ipsilateral primary motor cortex (M1). The magnitude and number of evoked muscle responses were associated with the stimulus intensity and number of pulses. The muscle responses were diminished during M1 inactivation. Thus, the present study has identified a multisynaptic VM-spinal pathway that is mediated, at least in part, by the M1 and might play a pivotal role in modulatory control of the spinal motor output. KEY POINTS: Motivation to obtain reward is thought to boost motor performance, and activity in the ventral midbrain is important to the motivational process. Little is known about a neural substrate bridging the ventral midbrain and the spinal motor output. Retrograde trans-synaptic experiments revealed that the ventral midbrain projects multisynaptically to the spinal cord in macaque monkeys. Ventral midbrain activation by electrical stimulation generated cortical activity in the motor cortex and forelimb muscle activity. A multisynaptic ventral midbrain-spinal pathway most probably plays a pivotal role in modulatory control of the spinal motor output.

G-CSF Production by Undifferentiated Pleomorphic Sarcoma with Leukemoid Reaction Occurred in the Lower Leg: A Case Report.

CASE: A 46-year-old woman presented with a mass in the lower leg and severe leukocytosis. Diffuse uptake in the bones was detected with F-fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) imaging. The serum granulocyte-colony stimulating factor (G-CSF) was elevated, and immunostaining for G-CSF was positive. When diagnosed as G-CSF-producing undifferentiated pleomorphic sarcoma (UPS), a wide resection was performed. The leukocytosis and serum G-CSF were remarkably improved after tumor resection. No local recurrence or metastasis was detected. CONCLUSION: We report the first case of inflammatory UPS in the extremity which demonstrated the neoplastic production of G-CSF. In our case, F-FDG PET/CT, the serum G-CSF, and immunostaining for G-CSF were useful for diagnosis.

The Ventral Striatum is a Key Node for Functional Recovery of Finger Dexterity After Spinal Cord Injury in Monkeys.

In a recent study, we demonstrated that the ventral striatum (VSt) controls finger movements directly during the early recovery stage after spinal cord injury (SCI), implying that the VSt may be a part of neural substrates responsible for the recovery of dexterous finger movements. The VSt is accepted widely as a key node for motivation, but is not thought to be involved in the direct control of limb movements. Therefore, whether a causal relationship exists between the VSt and motor recovery after SCI is unknown, and the role of the VSt in the recovery of dexterous finger movements orfinger movements in general after SCI remains unclear. In the present study, functional brain imaging in a macaque model of SCI revealed a strengthened functional connectivity between motor-related areas and the VSt during the recovery process for precision grip, but not whole finger grip after SCI. Furthermore, permanent lesion of the VSt impeded the recoveryof precision grip, but not coarse grip. Thus, the VSt was needed specifically for functional recovery of dexterous finger movements. These results suggest that the VSt is the key node of the cortical reorganization required for functional recovery of finger dexterity.

[A study of "sudden death" in end-stage cancer patients receiving home care].

We retrospectively examined the actual status and management of sudden changes in end-stage cancer patients receiving home care. We defined "sudden death" as an incident in which patients who had been ambulatory suddenly experienced a change in condition and died within a day. As per this definition, 32 of 130 end-stage cancer patients (24.6%) who died at home during a period of 2 years experienced "sudden death". The reasons for sudden changes included liver rupture, liver failure, hematemesis/melena, and renal failure. It was presumed that 87.5% of patients who experienced "sudden death" had a life expectancy of days or weeks. Those who experienced sudden change in the presence of their family and died immediately thereafter or were found in a state of respiratory arrest accounted for 43.8% of cases. At the time of sudden change, sedation was performed in 34.3% of cases. Patient families were generally able to take action in a calm manner. Healthcare professionals and patient families should always be aware of the possibility of sudden changes in end-stage cancer patients. In addition, it is important for healthcare professionals to confirm how patients and their families perceive the disease condition, provide pain relief, and support families who are upset and anxious at the time of sudden changes.

Addition of leukotriene receptor antagonists to inhaled corticosteroids improved QOL of patients with bronchial asthma surveyed in suburban Tokyo, Japan.

BACKGROUND: Bronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide. METHODS: A survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged ≥ 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated. RESULTS: Asthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by >80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting ß(2) agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA. CONCLUSIONS: These results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA.

[A case of pulmonary nocardiosis during steroid therapy for asthma].

A 76-year-old man had suffered from asthma since age 6. His asthma had recently worsened due to pneumonia. At a local clinic, he was given steroids and antibiotics for more than a week. Although his pneumonia improved, his asthma was not controlled, so he was admitted to our hospital. Steroid therapy was administered for about 2 weeks in an attempt to treat the asthma. From a chest x-ray film and CT scan it was apparent that multiple nodules had appeared in the lower lobes of both lungs. We performed bronchoscopy and Nocardia species were detected in both lower lobes of the lung from bronchoalveolar lavage. Pulmonary nocardiosis was diagnosed. We started treatment with sulfamethoxazole and trimethoprim. While the fever was reduced and the appearance of the chest X-ray improved, appetite loss became serious, so we changed the antibiotic regimen to imipenem/cilastatin and amikacin. Following this change in medication, the patient's fever increased again and the chest Xray findings regressed, so we changed his antibiotic regimen to minocycline. All symptoms improved thereafter. Nocardiosis often occurs in immunocompromised patients. Mortality is about 35%, so rapid diagnosis and appropriate treatment is necessary, but not always possible due to difficulties in diagnosis. The onset of lung nocardiosis is usually subacute. This case was caught comparatively early, because of the previous steroid treatment.