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Parkinson's disease (PD) reportedly includes altered connectivity of neural loops involving the basal ganglia and cerebellum, although little is known regarding any changes in the connectivity of motor loops. The goal of this study was to further understand the connectivity within the basal ganglia-thalamo-motor (BGTM) and cerebro-cerebellar (CC) loops in PD. Twelve PD patients and 12 age-matched control subjects performed a protocol involving self-initiated (SI) and externally-triggered (ET) finger movements, while being scanned with functional magnetic resonance imaging. Compared with the control subjects, the PD subjects showed hypo-activation in the bilateral putamen, right supplementary motor area and hyper-activation in the right premotor cortex. In the sensorimotor cortex and cerebellar hemisphere, PD subjects tended to show hyper-activation in a main effects analysis, but hypo-activation in a linear effects analysis. Analysis using structural equation modeling (SEM) revealed significant positive interactions within the right BGTM loop during the SI task and within the right (right cerebral hemisphere-left cerebellum) CC loop during the ET task. SEM also revealed task-related quantitative changes between the thalamus and the motor cortices in the control subjects. We found that the PD patients showed reduced connectivity in the right BGTM loop and inter-hemispheric connections in SEM, which is the first demonstration of this phenomenon. Interestingly, PD patients exhibited preserved connectivity within the right CC loop during the ET task. These results suggest disruption of cortico-striatal processing and preservation of relatively intact neural circuits that do not involve the basal ganglia in PD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We report a 47-year-old woman with progressive multifocal leukoencephalopathy (PML). She was a carrier of HTLV-I virus, and developed subacute right hemiparesis and marked motor aphasia. She had a malignant lymphoma in the left neck and basal cell carcinoma in the right inguinal region. Three months after the onset, she became unable to walk because of the right leg weakness or to speak because of motor aphasia. Magnetic resonance imaging (MRI) revealed multifocal T2-high lesions in the white matter of the left frontal lobe, and a brain biopsy revealed demyelinating pathology. A biopsy of the left parotid gland revealed a diffuse pleomorphic type large B cell lymphoma. Although anti-HTLV-I antibody was positive in the serum and cerebrospinal fluid (CSF), no adult T-cell leukemia (ATL) cells were found in the blood or CSF. The patient was then admitted to our hospital. Neurological examinations revealed severe motor aphasia, mild sensory aphasia/cognitive impairment, right hemiplegia, mild right hemihypesthesia, limb-kinetic apraxia in the left hand, idiomotor apraxia, agraphia, perseveration, marked spasticity and brisk tendon reflex in four extremities, and positive bilateral pathological reflexes. MRI showed multifocal T2-high lesions mainly in the cerebral white matter, predominantly in the left hemisphere, and partly in the cerebral cortex. No gadolinium enhancement was found. In addition, 99mTcECD-SPECT showed a broad decrease in cerebral blood flow (CBF) in the cortex. Anti-HTLV-I antibody was positive but anti-HIV antibody was negative in serum. ATL cells were found in 1-3% of the peripheral white blood cells after admission. CSF examination revealed that the cell count (1/microl), protein level (24 mg/dl), and IgG index (0.4) were all normal. However, the myelin basic protein level (321 pg/ml; normal < 102) was increased, JC virus DNA was detected by PCR, and anti-HTLV-I antibody (x 8) was detected in CSF. The regulatory region of the JC virus DNA in the CSF was partly deleted; immunostaining with anti-JC virus protein antibodies revealed the existence of JC virus in biopsied brain specimens, and these findings were consistent with PML. Her symptoms such as motor aphasia, cognitive dysfunction and left hemiparesis were subacutely progressive, and she developed akinetic mutism two weeks after admission. Since the efficacy of cytosine arabinoside for PML has been reported, she was administered 80 mg/day of the drug for five days. After treatment, her communication function was mildly improved but the efficacy was transient. Since it has been reported that HTLV-I, as well as HIV, activates the JC virus promoter and its proliferation, the latent infection of HTLV-I in the central nervous system (CNS) in this case might have stimulated the JC virus proliferation, promoting lesion extension over the cerebral cortex. There have been only a few reports of broad decreases in CBF by SPECT in PML patients. Further MRI and SPECT studies on PML patients are therefore necessary to evaluate the significance of HTLV-I in promoting the JC virus infiltration into the CNS.

Objective: To clarify the relationship between D2 receptor binding and the cerebral metabolic rate for glucose (CMRGlu) in patients with parkinsonism, we simultaneously measured both of these factors, and then compared the results., Methods: The subjects consisted of 24 patients: 9 with Parkinson's disease (PD), 3 with Juvenile Parkinson's disease (JPD), 9 with multiple system atrophy (MSA), and 3 with progressive supranuclear palsy (PSP). The striatal D2 receptor binding was measured by the C-11 raclopride transient equilibrium method. CMRGlu was investigated by the F-18 fluorodeoxyglucose autoradiographic method., Results: The D2 receptor binding in both the caudate nucleus and putamen showed a positive correlation with the CMRGlu in the PD-JPD group, but the two parameters demonstrated no correlation in the MSA-PSP group. The left/right (L/R) ratio of D2 receptor binding in the putamen showed a positive correlation with that of CMRGlu in the MSA-PSP group, while the two demonsrated no correlation in the PD-JPD group., Conclusion: Our PET study showed striatal D2 receptor binding and the CMRGlu to be closely related in patients with parkinsonism, even though the results obtained using the L/R ratios tended to differ substantially from those obtained using absolute values. The reason for this difference is not clear, but this finding may reflect the pathophysiology of these disease entities.

Rationale and Objective: Structure of the brain is generally thought to remain stationary over the course of young adulthood. However, there is some evidence that microstructural changes of the brain do occur during this period. Magnetic resonance diffusion tensor imaging (DTI) provides quantitative measures of structural changes in the brain. We used DTI to detect possible age-related structural changes in the brains of young adults., Materials and Methods: Twenty-five healthy adults in their 20s and 30s were studied using DTI. Maps of mean diffusivity and fractional anisotropy (FA) were created for subsequent histogram and region-of-interest analyses, and the results were correlated with the respective ages of the subjects., Results: The histogram analysis revealed a significant increase in the mean FA value (r = 0.407, P < .05) and a significant decrease in FA peak height (r = -0.578, P < .002) with increasing age. No age-related changes were observed in indices derived from mean diffusivity maps. Region-of-interest analysis showed no focal white matter regions with significant FA change., Conclusion: Quantitative DTI revealed age-related structural changes in the brains of young adults. Changes on FA histograms observed in this study were considered to be related to changes in the relative volumes of gray and white matter and may represent maturational changes.

Visual agnosia has been well studied by anatomical, neuropsychological and neuroimaging studies. However, functional changes in the brain have been rarely assessed by electrophysiological methods. We carried out electrophysiological examinations on a 23-year-old man with associative visual agnosia, prosopagnosia and cerebral achromatopsia to evaluate the higher brain dysfunctions of visual recognition. Electrophysiological methods consisted of achromatic, chromatic and category-specific visual evoked potentials (CS-VEPs), and event-related potentials (ERPs) with color and motion discrimination tasks. Brain magnetic resonance imaging revealed large white matter lesions in the bilateral temporo-occipital lobes involving the lingual and fusiform gyri (V4) and inferior longitudinal fasciculi due to multiple sclerosis. Examinations including CS-VEPs demonstrated dysfunctions of face and object perception while sparing semantic word perception after primary visual cortex (V1) in the ventral pathway. ERPs showed abnormal color perception in the ventral pathway with normal motion perception in the dorsal pathway. These electrophysiological findings were consistent with lesions in the ventral pathway that were detected by clinical and neuroimaging findings. Therefore, CS-VEPs and ERPs with color and motion discrimination tasks are useful methods for assessing the functional changes of visual recognition such as visual agnosia.

Objective: We examined the interhemispheric functional synchronization of the visual cortex using coherence (Coh) analysis., Methods: Achromatic or isoluminant chromatic sinusoidal grating stimuli were presented to each hemifield at a rate of 8 reversals/s to record steady-state visual-evoked potentials (S-VEPs) in 10 healthy subjects. Four recording electrodes were placed at O1, O2, P3 and P4, referred to an electrode at Cz. A total of 50 responses of 1 s epoch were averaged, and were subjected to discrete fast Fourier transforms to yield the amplitude and phase of the 8 Hz component. Ordinary and partial Coh values were also calculated., Results: For both achromatic and chromatic stimuli, the 8 Hz amplitudes of O1 and O2 were significantly larger than those of P3 and P4 without any significant difference between O1 and O2. The phase lag between O1 and O2 was approximately 30 degrees (latency shift 10.4 ms). Partial Coh between O1 and O2 at 8 Hz was significantly greater than that of the unstimulated condition, and this was only observed at 8 Hz., Conclusions: These results suggest that interhemispheric synchronization in the occipital area occurs despite the nature of the visual stimuli. Therefore, the activation of interhemispheric connection is important for the early stage of the visual information processing., Significance: Our results indicate that the first step of the visual information processing requires interhemispheric functional synchronization.

It has been reported that diffusion-weighted imaging (DWI) can detect white matter degeneration in the Alzheimer's disease (AD) brain. We hypothesized that imaging of the slow diffusion component using high b value DWI is more sensitive to AD-related white matter degeneration than is conventional DWI, and therefore we studied the effects of high b value on lesion-to-normal contrast and contrast-to-noise ratio (CNR). Seven AD patients and seven age-matched normal subjects were studied with full-tensor DWI at three different b values (1000, 2000, and 4000 s/mm(2)) without changing echo time or diffusion time, and the mean diffusivities in the parietal and occipital regions were measured. Statistical analyses revealed that use of higher b values significantly improves both lesion-to-normal contrast and CNR. We concluded that high b value DWI is more sensitive to AD-related white matter degeneration than is conventional DWI.

Previous positron emission tomography (PET) studies have shown widespread hypometabolism in the brain of advanced MSA but the time course of these metabolic abnormalities is largely unknown. In order to clarify the principal disease processes in multiple system atrophy (MSA) in the early stage, we investigated regional cerebral glucose metabolism (rCMGglc) and nigral dopaminergic function in nine patients with early stage of MSA using [(18)F]fluorodeoxyglucose (FDG) and 6-L-[(18)F]fluorodopa ((18)F-Dopa) positron emission tomography (PET) (two men and seven women; age, 59.3+/-5.4 years; disease duration, 29.7+/-14.6 months). The rCMRglc in the early MSA patients significantly decreased in the cerebellum, brainstem, and striatum compared with that in nine normal subjects. A significant correlation was found between the severity of autonomic dysfunction and rCMRglc within the brainstem. The severity of extrapyramidal signs also correlated with the decline of F-Dopa uptake but not that of rCMRglc within the striatum. The degree of atrophy on MRI has correlated with neither the clinical symptoms nor rCMRglc at the cerebellum and the brainstem. Our PET studies demonstrated widespread metabolic abnormalities except for the cerebral cortex in the brain of MSA even in the early stage. The hypometabolism in the brainstem was tightly linked to the autonomic dysfunction. Not the striatal dysfunction but the nigral damage may be responsible for the extrapyramidal symptoms in early MSA.

Objectives: The objective of the present study is to quantify the effects of voluntary muscle contraction of the small hand (abductor pollicis brevis, first dorsal interosseus (FDI)) and forearm muscles (extensor carpi radialis (ECR), extensor carpi ulnaris (ECU), flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU)) on motor evoked potentials (MEPs)., Methods: MEPs were recorded in 12 healthy subjects by a circular coil placed over the vertex at 1.2 times the resting motor threshold at different levels of the muscle contraction (0-100% of maximum voluntary contraction (MVC)). The effects of transcranial magnetic stimulation (TMS) on the onset latency, MEP area and silent period (SP) as a function of the %MVC were evaluated using a piecewise linear regression analysis., Results: The MEP areas for the small hand muscles were almost completely saturated at 20% of MVC. In contrast, the MEP areas for radial muscles (ECR, FCR) had a dual increase at 40% of MVC while the ulnar muscles (ECU, FCU) had a dual increase at 20% of MVC. A uniform latency shift (1.5-3 ms reduction) was observed in all muscles with a changing point at 10% of MVC. The SPs were the longest for FDI and were not significantly influenced by MVC for any muscles., Conclusions: The excitatory and inhibitory effects of TMS on the MEPs differed for the small hand and forearm muscles and also between the ulnar and radial muscles. These results probably resulted from the different degrees of direct corticomotoneuronal inputs to each muscle and the inherent properties of the spinal motoneurons.

Objectives: We studied the origin and underlying mechanism of the soleus late response (SLR) at a mean latency of 90 ms following transcranial magnetic stimulation., Methods: The soleus primary response (SPR) and SLR were recorded from the soleus (SOL) muscle in 27 normal subjects under various conditions using a double-cone coil. We also tested 28 patients demonstrating neurological disorders with postural disturbance., Results: The amplitude of the SPR gradually increased and its latency gradually decreased against the voluntary contraction (0-80%) of the tibialis anterior (TA) muscle. In contrast, the SLR amplitude was the greatest at a 20% TA contraction while the SLR latency was the shortest at a 40% TA contraction. The preactivation of SOL enhanced the SPR response but did not evoke the SLR. The SPR amplitude was significantly augmented while standing, however, the SLR amplitude tended to decrease. The SLR was never obtained following the stimulation of the brainstem, lumbar roots and peroneal nerve. The SLR was abnormal in patients with cerebellar ataxia and Parkinson's disease while the SPR was normal., Conclusions: A lack of any correlation between the SPR and SLR suggests that the SLR does not originate in the corticospinal tract. The SLR may thus be a polysynaptic response related to the postural control of the agonist and antagonist organization between the TA and SOL.

We report the case of a 60-year-old man with autopsy-proven dementia with motor neuron disease (D-MND) and Alzheimer's disease lesion. The patient presented with clumsiness of his right hand at the age of 55 years old and subsequently developed dysarthria, weakness and atrophy of his upper limbs. He was unaffectionate towards his family, repeated the same phrase, and showed severe disorientation of time and place. Neurological examination on admission showed not only diffuse lower motor neuron signs, such as weakness, atrophy, fasciculation and areflexia in both upper limbs, but also dementia (HDS-R 9/30). He died of respiratory insufficiency. Neuropathological examination showed mild atrophy of the frontal and temporal lobes and anterior spinal roots. Microscopic examination of cortical sections revealed degenerative changes with simple atrophy and gliosis, and these changes were predominant in layers 1 and 2 of the frontal and temporal cortices. Using immunohistochemical staining, ubiquitin-positive but tau-negative inclusions were frequently found in neurons of the hippocampal granular cell layers and temporal lobes. Many senile plaques and neurofibrillary tangles were present in all sections of the brain. Our final diagnosis was dementia with motor neuron disease accompanying Alzheimer's disease lesion, because of hypoperfusion in the parietal lobe as well as the frontal lobe demonstrated by SPECT, and the presence of many senile plaques and neurofibrillary tangles in the cerebral cortex. Overlapping of pathologically-proven D-MND and Alzheimer's disease lesion is extremely rare, and this case may improve our understanding of the process of neurodegeneration.

PET has been proved to be a powerful tool for exploring the brain function. We discussed the advantages and limitations of PET for analyzing the brain function on the basis of our clinical and experimental experiences of functional imaging. A multimodality PET study measuring cerebral energy metabolism (CMRO2 and CMRglc), cerebral blood flow (CBF), oxygen extraction fraction (OEF) and neurotransmitter function (presynaptic and postsynaptic) opens up a closer insight into a precise pathophysiology of the brain dysfunction: In cerebral infarction, it reveals a state of "misery perfusion" in the acute stage, "luxury perfusion" in the intermediate stage, and proportionately decreased CBF and CMRO2 in the chronic stage. Neurotransmitter function may identify specifically a neuronal subgroup of dysfunction. Owing to the low temporal resolution of PET, a neuronal activity may propagate transsynaptically to remote areas during the period of scanning, resulting in an obscured primary site of the neuronal activity. Uncoupling between neuronal activities and cerebral energy metabolism/CBF may occur under a certain state of brain pathology, particularly after an acute destructive lesion, according to our experimental studies. Neurotransmitter function may reveal the effect of drugs on the brain function, and may be useful for developing a new method of drug therapy for brain diseases in the future.

A specific subset of neuropeptides are expressed in astrocytes, with specificity in terms of both brain region and gene, as well as with specific developmental patterns: the overall pattern of expression is thus heterogeneous. These neuropeptides have been demonstrated to have a number of trophic effects, including regulation of cell number, of length of axons and dendrites, and of neuronal phenotype. The developmental regulation of expression of neuropeptides in astrocytes further supports functional roles for the neuropeptides as trophic modeling factors. Not all the trophic effects have to be stimulatory and evidence suggests that opioid peptides may function to prune dendrites or decrease cell numbers in order to modulate or shape the nervous system. In addition to roles during development, preliminary experiments suggest that astrocyte neuropeptide expression turns back on in the adult brain following injury, suggesting that the neuropeptides may play a role in supporting survival or recovery of damaged neurons. The heterogeneity of neuropeptide expression in astrocytes must therefore contribute to the establishment and maintenance of the network of communication among neurons and glia in the nervous system in ways we have yet to understand fully.