Altered functional connectivity associated with striatal dopamine depletion in Parkinson's disease.

We aimed to clarify whether dopamine depletion in the posterior dorsal striatum in early-stage Parkinson's disease (PD) alters synchronized activity in the cortico-basal ganglia motor circuit. In sum, 14 PD patients and 16 matched healthy controls (HC) underwent [11C]-2-ß-carbomethoxy-3-ß-(4-fluorophenyl) tropane positron emission tomography to identify striatal dopamine-depleted areas. The identified map was applied to functional magnetic resonance imaging (fMRI) to discover abnormalities in functional connectivity (FC) during motor-task and rest-state in PD patients in the drug-off state relative to HC. Striatal dopamine-depleted areas formed synchronized fMRI activity that largely corresponded to the cortico-basal ganglia motor circuit. Group comparisons revealed that striatal dopamine-depleted areas exhibited decreased FC with the medial premotor cortex during motor-task and with the medial, lateral premotor and primary motor cortices during rest-state. Striatal dopamine-depleted areas also elucidated decreased FC in the subthalamic nucleus (STN) in PD both during motor-task and rest-state. The STN regions that exhibited reduced FC with striatal dopamine-depleted areas demonstrated excessive FC with the lateral premotor and primary motor cortices in PD only during rest-state. Our findings suggest that striatal dopamine-depleted area reduced synchronized activity with the motor cortices and STN, which, in turn, induces an abnormal increase in coupling between the areas in PD.

Successful treatment of tuberculous meningitis in an Indian female under hemodialysis therapy.

Hemodialysis is a well-known risk factor for severe infection by putting patients under an immunocompromised state. Such patients are prone to opportunistic pathogen and present with atypical manifestations during infection. Tuberculous meningitis is a central nervous system infection of Mycobacterium tuberculosis, accounting for the highest mortality of all forms of tuberculosis. In fact, the mortality rate of tuberculous meningitis in hemodialysis patients is extremely poor because early clinical diagnosis is difficult. Here, we report a case of tuberculous meningitis in a 61-year-old Indian hemodialysis patient, who presented with fever of unknown origin and was successfully treated with empiric treatment with standard four-drug regimen against tuberculosis. Comprehensive screening of the origin of fever revealed only the positive results of interferon-gamma release assay, which led us to initiate an empiric therapy for tuberculosis, before making a definitive diagnosis by cerebrospinal fluid nested PCR. Soon after the initiation of the treatment, the fever immediately abated. Although the patient experienced a single episode of paradoxical worsening and severe liver injury, she recovered well without any complications. This report provides a clinical course of the disease in a hemodialysis patient, highlighting the importance of early clinical diagnosis and rapid initiation of empirical tuberculosis treatment.

Diagnosis of Spontaneous Cerebrospinal Fluid Rhinorrhea Using Thin-Slice Computed Tomographic Images With Multiplanar Reconstruction and Three-Dimensional Virtual View Endoscopy.

Spontaneous cerebrospinal fluid (CSF) rhinorrhea represents an important clinical entity, which is associated with elevated intracranial pressure and is rarely treated successfully without surgical intervention. Here we report a case of spontaneous CSF rhinorrhea. The patient was a 54-year-old male, who presented with bacterial meningitis and was referred to the Department of Otorhinolaryngology for a detailed examination of the nose and sinuses. Reconstructed thin-slice computed tomography (CT) revealed multiple fistulae on the clivus. The defect was successfully repaired by transnasal endoscopic surgery, with the assistance of virtual endoscopic images, which were created by the surgical planning and navigation system from thin-slice CT images. This incremental improvement in the imaging technique helped with the diagnosis and surgical treatment of CSF rhinorrhea.

Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia.

Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.

Antidepressants for Depression, Apathy, and Gait Instability in Parkinson's Disease: A Multicenter Randomized Study.

Objective Depression, apathy, and gait instability are cardinal symptoms in patients with Parkinson's disease (PD). Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are used for treating the psychiatric symptoms of PD. This is the first prospective randomized study to compare the efficacy of an SNRI (duloxetine) with SSRIs (paroxetine, escitalopram) in improving depressive symptoms and apathy (primary) and freezing of gait (FOG; secondary) in patients with PD. Methods In this prospective, multicenter, open-label, randomized study, Japanese PD patients with a Quick Inventory of Depressive Symptomatology-Japanese (QIDS-J) score ≥6 were randomly assigned to receive an SSRI (27 enrolled, 25 analyzed) or duloxetine (28 enrolled, 27 analyzed) and were assessed at 6 and 10 weeks. Results The mean change (SD) in the QIDS J [SSRI -2.4 (3.6), p=0.015; SNRI -2.3 (3.9), p=0.029] and FOG-Questionnaire [SSRI -2.9 (4.2), p=0.012; SNRI -3.4 (4.7), p=0.010] scores (from baseline) at 10 weeks was statistically significant, while the mean change in the Apathy Scale scores was not [SSRI -2.7 (5.4), p=0.054; SNRI -1.5 (3.7), p=0.109]. No significant differences were observed between the SSRI and SNRI groups. The treatments were well-tolerated; however, gastrointestinal events were more common with SSRIs. Two SNRI-treated patients reported an exacerbation of tremor. Conclusion SSRIs and SNRIs improve the depressive symptoms and FOG in PD patients with mild to severe depressive symptoms. However, their effectiveness in treating apathy remains to be elucidated.

Interhemispheric Resting-State Functional Connectivity Predicts Severity of Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by a clinical triad (gait disturbance, dementia, and urinary incontinence), and by radiological findings of enlarged ventricles reflecting disturbance of central spinal fluid circulation. A diagnosis of iNPH is sometimes challenging, and the pathophysiological mechanisms underlying the clinical symptoms of iNPH remain largely unknown. Here, we used an emerging MRI technique, resting-state functional connectivity MRI (rsfcMRI), to develop a subsidiary diagnostic technique and to explore the underlying pathophysiological mechanisms of iNPH. rsfcMRI data were obtained from 11 patients with iNPH and 11 age-matched healthy volunteers, yielding rsfcMRI-derived functional connectivity (FC) from both groups. A linear support vector machine classifier was trained to distinguish the patterns of FCs of the patients with iNPH from those of the healthy volunteers. After dimensional reduction, the support vector machine successfully classified the two groups with an accuracy of 80%. Moreover, we found that rsfcMRI-derived FC carried information to predict the severity of the triad in iNPH. FCs relevant to the classification of severity were mainly based on interhemispheric connectivity, suggesting that disruption of the corpus callosum fibers due to ventricular enlargement may explain the triad of iNPH. The present results support the usefulness of rsfcMRI as a tool to understand pathophysiology of iNPH, and also to help with its clinical diagnosis.

Altered striatal circuits underlie characteristic personality traits in Parkinson's disease.

Patients with Parkinson's disease (PD) have been suggested to share personality traits characterised by low novelty-seeking and high harm-avoidance. Although a link between novelty-seeking and dopamine is hypothesised, the link is not fully supported by 6-[(18)F]fluoro-L-dopa positron emission tomography (PET) studies. Meanwhile, tractography studies with magnetic resonance imaging (MRI) link personality to the connectivity of the striatum in healthy subjects. Here, we investigated neurochemical and anatomical correlates of characteristic personality traits in PD. Sixteen PD patients and 28 healthy controls were assessed using the Temperament and Character Inventory. All patients and 17 randomly selected controls were scanned with 2ß-carbomethoxy-3ß-(4-fluorophenyl)-[N-(11)C-methyl]tropane ([(11)C]CFT) PET to measure striatal dopamine transporter availability. All subjects were scanned with MRI to evaluate the connectivity of the striatum using probabilistic tractography. PET findings revealed no correlation of novelty-seeking and harm-avoidance with [(11)C]CFT uptake in patients or controls. Novelty-seeking correlated positively with the connectivity strength of the striatum with the hippocampus and amygdala in both patients and controls. Harm-avoidance and the fibre connectivity strength of the striatum including ventral area with the amygdala correlated negatively in patients and positively in controls, which differed significantly between the groups. Our data support the notion that the fibre connectivity of the striatum with limbic and frontal areas underlies the personality profile. Furthermore, our findings suggest that higher harm-avoidance in PD is linked to alterations of the network, including the nucleus accumbens and amygdala.

Parkinson's disease patients showed delayed awareness of motor intention.

Although dopamine plays an important role for motor control and modulates the frontal function via basal ganglia-thalamo-cortical loop, it is not known whether dopamine can affect the awareness of motor intention or not. To test this hypothesis, we applied Libet's clock paradigm to Parkinson's disease (PD) patients. Thirteen PD patients and 13 age-matched, healthy controls took part in the experiment which consisted of three judgment paradigms: W, M and S judgment. In W and M judgments, subjects were asked to press the key at self-willed timing. In W judgment, subjects reported the location of the clock's hand when they became aware of the intention (W-time). In M judgment, subjects reported the time when they became aware of the actual movement (M-time). In S judgment, subjects reported the time of the electrical stimulation given to their hand (S-time). W-time was significantly shorter in PD patients than in healthy control subjects while M-time and S-time were not different between the two groups. Delayed awareness of motor intention but not of action in PD patients might be related to dopamine depletion in those patients.

Overlapping connections within the motor cortico-basal ganglia circuit: fMRI-tractography analysis.

Contribution of the subcortical nuclei to the coordination of human behavior is dependent on the existence of appropriate anatomical architecture. Interpretations of available data have led to opposing 'information funneling' and 'parallel processing' hypotheses. Using motor circuit as a model, we examined whether cortico-subcortical circuits, especially cortico-basal ganglia circuits, are funneled or parallel in the control of volitional movement. Twenty-five healthy subjects underwent functional magnetic resonance imaging (fMRI). Activated clusters during self-initiated, sequential finger-to-thumb opposition movements of the left hand were identified in the bilateral supplementary motor area (SMA), right lateral premotor cortex (PM) and primary motor cortex (M1), and in the right striatum and thalamus. These functionally defined clusters were applied to probabilistic tractography based on diffusion-weighted MRI to examine patterns of connectivity. Striatal and thalamic sub-regions with high probabilities of connection to the motor cortices partially overlapped, with connection to the two premotor areas outspreading rostrally relative to M1. We suggest that, on a macroscopic anatomical level, there is overlap as well as segregation among connections of the motor cortices with the striatum and thalamus. This supports the notion that neuronal information of the motor cortices is funneled, and parallel processing is not an exclusive principle in the basal ganglia.

Disseminated Nocardia farcinica infection in a patient with myasthenia gravis successfully treated by linezolid: a case report and literature review.

Nocardiosis is increasingly being diagnosed because of a growing population of immunocompromised hosts and improvements in the detection of Nocardia species in clinical laboratories. Historically, sulphonamides have been the first-line therapy for the treatment of nocardiosis, but sulphonamides tend to have a high rate of drug allergy in clinical settings. In this report, we described a disseminated Nocardia farcinica infection that occurred in a patient with myasthenia gravis who suffered from multiple drug allergies and was successfully treated using linezolid. We undertook a review of the literature of previously reported cases of nocardiosis treated with linezolid. To date, only 15 cases of nocardiosis treated with linezolid have been published. All cases exhibited long-term tolerance of linezolid, and 14 of 15 cases showed either an improvement in or complete clearance of the infection. According to the literature review, linezolid is an attractive alternative to trimethoprim-sulfamethoxazole for the treatment of disseminated nocardiosis, despite limited clinical evidence to support this claim.

Common inhibitory prefrontal activation during inhibition of hand and foot responses.

Previous neuroimaging studies using manual Stop signal task showed the inhibitory-related areas in the pre-supplementary motor area (pre-SMA) and ventrolateral prefrontal cortex (VLPFC). However, most previous studies employed the manual response inhibition task and the brain representation of the response inhibition of the other body parts has been rarely studied. To further understand the precise brain processing of response inhibition, we performed the event-related fMRI study of Stop signal tasks using the hand and foot response to reveal the common prefrontal region relevant for response inhibition in 13 subjects. We found that the pre-SMA and bilateral VLPFC were commonly activated in successful response inhibition both for hand and foot tasks. The comparison of brain activation between hand and foot response inhibition tasks did not show any significant difference in the prefrontal area. In addition, there was no significant difference for peak coordinates in the pre-SMA and bilateral VLPFC between hand and foot tasks. These findings indicate the common neural network for inhibition of initiated responses regardless of the hand and foot.

Functional relevance of pre-supplementary motor areas for the choice to stop during Stop signal task.

There exists an ongoing debate about the functional relevance of the pre-supplementary motor area (pre-SMA) and right ventrolateral prefrontal cortex (VLPFC) for response inhibition during Stop signal task, because of difficulties in segregating cognitive elements involved in stopping, such as response inhibition, attentional control and error monitoring. To further understand the precise brain representation of response inhibition, we developed a new "Double-press signal task" that requires subjects to decide pressing the button once or twice as quickly as possible according to the cue and conducted an event-related functional MRI study of the conventional Stop signal and Double-press signal tasks for 13 healthy subjects. The advantage of our experimental design is that the latter task does not contain any response inhibition and that its difficulty measured by error rate is not significantly different from that of Stop signal task. Activations of the right VLPFC and pre-SMA were observed only for Stop signal task. Moreover, voxel-by-voxel analysis comparing these two tasks showed the significantly larger activation in the pre-SMA for Stop signal task, supporting the hypothesis that the pre-SMA is functionally essential for response inhibition.