Yoshino Ueki

Altered plasticity of the human motor cortex in Parkinson's disease

Interventional paired associative stimulation (IPAS) to the contralateral peripheral nerve and cerebral cortex can enhance the primary motor cortex (M1) excitability with two synchronously arriving inputs. This study investigated whether dopamine contributed to the associative long‐term potentiation–like effect in the M1 in Parkinsons disease (PD) patients. Eighteen right‐handed PD patients and 11 right‐handed age‐matched healthy volunteers were studied. All patients were studied after 12 hours off medication with levodopa replacement (PD‐off). Ten patients were also evaluated after medication (PD‐on). The IPAS comprised a single electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 milliseconds (240 paired stimuli every 5 seconds for 20 minutes). The motor‐evoked potential amplitude in the right abductor pollicis brevis muscle was increased by IPAS in healthy volunteers, but not in PD patients. IPAS did not affect the motor‐evoked potential amplitude in the left abductor pollicis brevis. The ratio of the motor‐evoked potential amplitude before and after IPAS in PD‐off patients increased after dopamine replacement. Thus, dopamine might modulate cortical plasticity in the human M1, which could be related to higher order motor control, including motor learning. Ann Neurol 2006

Effects of aging on the human motor cortical plasticity studied by paired associative stimulation

OBJECTIVE To test whether the normal aging itself may change the cortical plasticity in human. METHODS Motor-evoked potentials (MEPs) were measured from 48 right-handed healthy volunteers (age 21-79) before and after the paired associative stimulation (PAS), comprising a single electric stimulus to the right median nerve at wrist and subsequent transcranial magnetic stimulation (TMS) of the left primary motor cortex. RESULTS The magnitude of MEP increased by PAS in the young and middle but not in the elderly and its change was negatively correlated with the age. CONCLUSIONS These results suggest that the human M1 shows age-dependent reduction of cortical plasticity. SIGNIFICANCE The reduction of the M1 plasticity may be caused by the attenuated responsiveness of intracortical circuits in the M1 and/or disrupted sensorimotor integration within basal ganglia-thalamocortical loop.

Disordered plasticity in the primary somatosensory cortex in focal hand dystonia

Interventional paired associative stimulation (PAS) can induce plasticity in the cortex, and this plasticity was previously shown to be disordered in the primary motor cortex in focal hand dystonia (FHD). This study aimed to test whether associative plasticity is abnormal in the primary somatosensory cortex (S1) in FHD and whether PAS modulates excitatory or inhibitory interneurons within the cortex. Ten FHD patients and 10 healthy volunteers were studied. We investigated the changes in single- and double-pulse somatosensory-evoked potentials before and after PAS, which consisted of peripheral electrical nerve stimulation and subsequent transcranial magnetic stimulation over S1. Four sessions of somatosensory-evoked potentials recordings were performed: before PAS, and immediately, 15 and 30 min after PAS. We compared the time course of the somatosensory-evoked potentials between the FHD and healthy groups. In the single-pulse condition, the P27 amplitudes were significantly higher in FHD immediately after PAS than before PAS, while no changes were observed in healthy subjects. In the double-pulse condition, significant differences in the suppression ratio of P27 were found immediately after and 15 min after PAS, while there were no significant differences in healthy subjects. The P27 suppression tended to normalize toward the level of the healthy volunteer group. In FHD, PAS transiently induced an abnormal increase in excitability in S1. In addition, intracortical inhibition in S1 was found to increase as well. This abnormal plasticity of the intracortical neurons in S1 may contribute to the pathophysiology of dystonia.

Movement-Related Cortical Stimulation Can Induce Human Motor Plasticity

Repeated paired associative stimulation combining peripheral nerve stimulation and transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can produce human motor plasticity. However, previous studies used paired artificial stimuli, so that it is not known whether repetitive natural M1 activity associated with TMS can induce plasticity or not. To test this hypothesis, we developed a movement-related cortical stimulation (MRCS) protocol, in which the left M1 was stimulated by TMS at specific timing with respect to the mean expected reaction time (RT) of voluntary movement during a simple reaction time task using the right abductor pollicis brevis (APB) muscle. Seventeen normal volunteers were subjected to repeated MRCS intervention (0.2 Hz, 240 pairs). Motor function was assessed before and after MRCS. When TMS was given 50 ms before the RT of movement [MRCS(−50)], motor-evoked potential (MEP) amplitude of the right APB, but not other muscles, increased for up to 15 min post-MRCS. The RT of the right APB was also shortened. However, spinal excitability measured by F-wave did not change. When TMS was given 100 ms after the RT [MRCS(+100)], MEP amplitude was decreased. These findings show that this new MRCS protocol can produce timing-dependent motor associative plasticity, which may be clinically useful.

Characteristics of the sequence effect in Parkinson's disease.

The sequence effect (SE) in Parkinsons disease (PD) is progressive slowing of sequential movements. It is a feature of bradykinesia, but is separate from a general slowness without deterioration over time. It is commonly seen in PD, but its physiology is unclear. We measured general slowness and the SE separately with a computer‐based, modified Purdue pegboard in 11 patients with advanced PD. We conducted a placebo‐controlled, four‐way crossover study to learn whether levodopa and repetitive transcranial magnetic stimulation (rTMS) could improve general slowness or the SE. We also examined the correlation between the SE and clinical fatigue. Levodopa alone and rTMS alone improved general slowness, but rTMS showed no additive effect on levodopa. Levodopa alone, rTMS alone, and their combination did not alleviate the SE. There was no correlation between the SE and fatigue. This study suggests that dopaminergic dysfunction and abnormal motor cortex excitability are not the relevant mechanisms for the SE. Additionally, the SE is not a component of clinical fatigue. Further work is needed to establish the physiology and clinical relevance of the SE.

Neural correlates of regional EEG power change

To clarify the physiological significance of task-related change of the regional electroencephalogram (EEG) rhythm, we quantitatively evaluated the correlation between regional cerebral blood flow (rCBF) and EEG power. Eight subjects underwent H2 15O positron emission tomography scans simultaneously with EEG recording during the following tasks: rest condition with eyes closed and open, self-paced movements of the right and left thumb and right ankle. EEG signals were recorded from the occipital and bilateral sensorimotor areas. Cortical activation associated with EEG rhythm generation was studied by the correlation between rCBF and EEG power. There were significant negative correlations between the sensorimotor EEG rhythm at 10-20 Hz on each side and the ipsilateral sensorimotor rCBF and between the occipital EEG rhythm at 10-20 Hz and the occipital rCBF. The occipital EEG rhythm showed a positive correlation with the bilateral medial prefrontal rCBF, while the right sensorimotor EEG rhythm showed a positive correlation with the left prefrontal rCBF. In conclusion, decrease in the regional EEG rhythm at 10-20 Hz might represent the neuronal activation of the cortex underlying the electrodes, at least for the visual and sensorimotor areas. The neural network including the prefrontal cortex could play an important role to generate the EEG rhythm.

Human motor associative plasticity induced by paired bihemispheric stimulation

Paired associative stimulation (PAS) is an effective non‐invasive method to induce human motor plasticity by the repetitive pairing of peripheral nerve stimulation and transcranial magnetic stimulation (TMS) at the primary motor cortex (M1) with a specific time interval. Although the repetitive pairing of two types of afferent stimulation might be a biological basis of neural plasticity and memory, other types of paired stimulation of the human brain have rarely been studied. We hypothesized that the repetitive pairing of TMS and interhemispheric cortico‐cortical projection or paired bihemispheric stimulation (PBS), in which the right and left M1 were serially stimulated with a time interval of 15 ms, would produce an associative long‐term potentiation (LTP)‐like effect. In this study, 23 right‐handed healthy volunteers were subjected to a 0.1 Hz repetition of 180 pairings of bihemispheric TMS, and physiological and behavioural measures of the motor system were compared before, immediately after, 20 min after and 40 min after PBS intervention. The amplitude of the motor evoked potential (MEP) induced by the left M1 stimulation and its input–output function increased for up to ∼20 min post‐PBS. Fine finger movements were also facilitated by PBS. Spinal excitability measured by the H‐reflex was insensitive to PBS, suggesting a cortical mechanism. The associative LTP‐like effect induced by PBS was timing dependent, occurring only when the interstimulus interval was 5–25 ms. These findings demonstrate that using PBS in PAS can induce motor cortical plasticity, and this approach might be applicable to the rehabilitation of patients with motor disorders.

Pasteurella multocida meningitis caused by kissing animals: a case report and review of the literature

Pasteurella multocida is a rare cause of meningitis. It is a Gram-negative coccobacillus that is a normal inhabitant of the nasopharynx or gastrointestinal tracts in animals. In humans, P. multocida has been reportedly responsible for secondary infections via domestic animals. Although it generally shows low pathogenicity in healthy individuals, exposure to domestic animals may increase the risk of infection. P. multocida should be considered as a potential cause of meningitis when a patient has experienced close contact with animals. A 44 year-old female complained of severe headache with nausea. Physical examination showed high-grade fever but no infectious symptoms and no signs of scratch wounds. She was alert and focal neurological signs were absent, but she complained of neck stiffness. Laboratory examination revealed a white blood cell count of 14,200/ mm (89.6% neutorophils), 4.2% HbA1c, and a negative HIV-1 serology. Chest X-ray and brain computed tomography findings were also normal. An initial cerebrospinal fluid (CSF) examination showed 2,880 cells/ll, an elevated protein level (156 mg/dl), and reduced glucose (51 mg/dl). Gram-negative rods were detected in the CSF by Gramstaining. The patient was therefore diagnosed with bacterial meningitis. Empiric therapy was started immediately with antibiotics, including high-dose meropenem (4 g/day) and vancomycin (2 g/day). P. multocida was isolated from blood and CSF. Based on the results of antibiotic susceptibility tests, meropenem treatment was continued for a week. Closer inspection revealed no underlying disease causing the bacterial meningitis. Her condition improved, with no neurological sequelae. On interview, she was found to have a habit of kissing her dog’s face and feeding it by transferring food mouth-to-mouth. The current case shows the typical symptoms and CSF findings of bacterial meningitis. Pasteurella multocida was isolated as the causative microorganism. Pasteurella multocida very occasionally produces infectious disease in humans, but its carriage rate in dogs, especially in the oral cavity, is high (12–75%) [3]. There have been some reports of animal bites resulting in symptoms of P. multocida infection in humans, including sepsis and cellulitis [5]. An overview of the literature on P. multocida meningitis between 1989 and 2009 suggests that animal kissing, as well as animal bites, can also cause this type of meningitis in healthy adults (Table 1) [1, 2, 6–10]. Patients with P. multocida meningitis occasionally have other, concomitant neurological diseases, such as epidural empyema and/ or encephalitis (Table 1) [2, 6–10]. Green et al. [2] reported that neurological complications were present in 17% (5/17 cases) of patients of P. multocida meningitis, based on an overview of case reports between 1989 and 1999. Analysis of a further 36 cases, in addition to the seven cases from 2000 to 2009, suggested a prevalence of neurological complications in patients with P. multocida of 22.2% (8/36 cases), which is similar to the reported prevalence in patients with bacterial meningitis caused by common bacteria. Penicillin was the most frequently used therapy in patients with P. multocida meningitis (Table 1) [2, 6–10]. However, penicillin-resistant P. multocida have been reported in rare cases [4]. We used meropenem and vancomycin as empiric antibiotics, to provide initial, broadspectrum coverage. S. Kawashima N. Matsukawa (&) Y. Ueki M. Hattori K. Ojika Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan e-mail: norim@med.nagoya-cu.ac.jp

Changes in Striatal Dopamine Release Associated with Human Motor-Skill Acquisition

The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using 11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The 11C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that 11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition.

Effect of spatial attention on human sensorimotor integration studied by transcranial magnetic stimulation.

OBJECTIVE Recent transcranial magnetic stimulation (TMS) studies showed that the sensory input can decrease the motor cortex excitability (afferent inhibition). To clarify the effect of attention on sensorimotor integration, we investigated the effect of spatial attention on afferent inhibition. METHODS Right median nerve electrical stimulation followed, at variable delays (10-300 ms), by TMS over the left motor cortex was applied to 9 subjects, during 3 conditions; spatial attention to the right and left hand, and control (no attention) tasks. RESULTS Inhibition of the motor evoked potential occurred at inter-stimulus interval of 20 and 100 ms, which was more was marked during spatial attention to the right than to the left hand. CONCLUSIONS Enhancement of the afferent inhibition induced by spatial attention to the stimulated side is likely to reflect the interaction between attention and sensorimotor integration. SIGNIFICANCE The spatial attention may modulate the sensorimotor integration studied by afferent inhibition of the MEP.