Freezing of gait and white matter changes: a tract-based spatial statistics study.

BACKGROUND: We hypothesized that the integrity of white matter might be related to the severity of freezing of gait in age-related white matter changes. METHODS: Twenty subjects exhibiting excessive hyperintensities in the periventricular and deep white matter were recruited. The subjects underwent the Freezing of Gait Questionnaire, computerized gait analyses, and diffusion tensor magnetic resonance imaging. Images of axial, radial and mean diffusivity, and fractional anisotropy were calculated as indices of white matter integrity and analyzed with tract-based spatial statistics. RESULTS: The fractional anisotropy, mean, axial and radial diffusivity averaged across the whole white matter structure were all significantly correlated with Freezing of Gait Questionnaire scores. Regionally, a negative correlation between Freezing of Gait Questionnaire scores and fractional anisotropy was found in the left superior longitudinal fasciculus beneath the left premotor cortex, right corpus callosum, and left cerebral peduncle. The scores of the Freezing of Gait Questionnaire were positively correlated with mean diffusivity in the left corona radiata and right corpus callosum, and with both axial and radial diffusivity in the left corona radiata. The white matter integrity in these tracts (except the corpus callosum) showed no correlation with cognitive or other gait measures, supporting the specificity of those abnormalities to freezing of gait. CONCLUSION: Divergent pathological lesions involved neural circuits composed of the cerebral cortex, basal ganglia and brainstem, suggesting that freezing of gait has a multifactorial nature.

Cognitive dysfunction associated with anti-glutamic acid decarboxylase autoimmunity: a case-control study.

BACKGROUND: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA). Anti-GAD antibodies (GADA) are associated with the progression of stiff person syndrome and other neurological diseases, as well as the immune-mediated (type 1) diabetes. GABA is one of the most widely distributed neurotransmitters, but the non-motor symptoms of GADA-positive patients are not well understood. Diabetes is increasingly recognized as a risk factor for dementia; however, the relationship between diabetes and dementia is controversial.The objective of this study was to assess cognitive function in patients with GADA-positive diabetes using subjects with GADA-negative type 2 diabetes as controls. METHODS: Twenty-one patients with GADA-positive diabetes (mean age 52.5 ± 12.3 years, mean duration 7.7 ± 6.6 years) and 19 control subjects with GADA-negative type 2 diabetes (mean age 53.4 ± 8.9 years, mean duration 12.5 ± 6.7) were included in the study. The subjects underwent extensive neuropsychological testing and brain MRI. RESULTS: The neuropsychological test scores were lower in the GADA-positive group than the control group (GADA-negative). Twelve subjects (57%) in the GADA group and 4 subjects (21%) in the control group had low performances (p = 0.027). No statistically significant differences were found between the GADA and control groups regarding demographics, diabetic severity cardiovascular risks, cerebral T2 hyperintensities, white matter volume and gray matter volume. CONCLUSIONS: Our study showed that GADA-positive diabetic patients have an increased risk of cognitive decline compared to patients with type 2 diabetes of comparable diabetic severity. It also showed that GADA may be associated with isolated cognitive decline in the absence of other neurological complications.

Controlled study of 50-Hz repetitive transcranial magnetic stimulation for the treatment of Parkinson disease.

OBJECTIVE: To investigate the safety and efficacy of 50-Hz repetitive transcranial magnetic stimulation (rTMS) in the treatment of motor symptoms in Parkinson disease (PD). BACKGROUND: Progression of PD is characterized by the emergence of motor deficits that gradually respond less to dopaminergic therapy. rTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Prior controlled studies suggest that an increase in stimulation frequency might enhance therapeutic efficacy. METHODS: In this randomized, double blind, sham-controlled study, the authors investigated the safety and efficacy of 50-Hz rTMS of the motor cortices in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neurophysiological, and neuropsychological parameters. In addition, the safety of 50-Hz rTMS was tested with electromyography-electroencephalogram (EMG-EEG) monitoring during and after stimulation. RESULTS: The authors investigated 26 patients with mild to moderate PD: 13 received 50-Hz rTMS and 13 sham stimulation. The 50-Hz rTMS did not improve gait, bradykinesia, and global and motor UPDRS, but there appeared a short-lived "on"-state improvement in activities of daily living (UPDRS II). The 50-Hz rTMS lengthened the cortical silent period, but other neurophysiological and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects. CONCLUSION: It appears that 50-Hz rTMS of the motor cortices is safe, but it fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious but need to be established in future research.

Development of a VR-based treadmill control interface for gait assessment of patients with Parkinson's disease.

Freezing of gait (FOG) is a commonly observed phenomenon in Parkinson's disease, but its causes and mechanisms are not fully understood. This paper presents the development of a virtual reality (VR)-based body-weight supported treadmill interface (BWSTI) designed and applied to investigate FOG. The BWSTI provides a safe and controlled walking platform which allows investigators to assess gait impairments under various conditions that simulate real life. In order to be able to evoke FOG, our BWSTI employed a novel speed adaptation controller, which allows patients to drive the treadmill speed. Our interface responsively follows the subject's intention of changing walking speed by the combined use of feedback and feedforward controllers. To provide realistic visual stimuli, a three dimensional VR system is interfaced with the speed adaptation controller and synchronously displays realistic visual cues. The VR-based BWSTI was tested with three patients with PD who are known to have FOG. Visual stimuli that might cause FOG were shown to them while the speed adaptation controller adjusted treadmill speed to follow the subjects' intention. Two of the three subjects showed FOG during the treadmill walking.

[The functional significance of the basal ganglia-thalamo-cortical loop in gait control in humans: a neuroimaging approach].

The basic locomotor modules located in the brainstem and the spinal cord can control elements of gait movement independently from other structures. Although these locomotor modules are considered to be acquired innately, their higher-level control is important in primates, especially in humans, who employ bipedal gait to adapt to the external environment. The basal ganglia-thalamo-cortical loops are involved in higher-leveled gait control. These loops are composed of several parallel, segregated, and functionally distinct, but homologous, neural circuits. The motor loop originates from the motor cortices, namely, the primary motor cortex, supplementary motor area (SMA), and lateral premotor cortex, and projects to the somatomotor region of the basal ganglia, thereby controlling voluntary movement. Dysfunction of the basal ganglia-thalamo-SMA loop results in gait disturbance in Parkinson disease and vascular parkinsonism. The dysfunction of the SMA loop could be compensated for by the activation of the lateral premotor cortex, the function of which appears to be preserved under appropriate external stimuli in parkinsonian patients.

Gait disturbance associated with white matter changes: a gait analysis and blood flow study.

To clarify the mechanisms underlying gait disturbance secondary to age-related white matter changes (ARWMC), cerebral perfusion was investigated during treadmill walking. Twenty subjects with extensive hyperintensities in the periventricular and deep white matter on T(2)-weighted magnetic resonance images (MRI) were recruited. The ARWMC subjects were classified into gait-disturbed (GD) and non-GD groups according to clinical criteria. All the subjects underwent gait analyses and cerebral perfusion measurements during both gait and rest by using single photon emission computed tomography. The GD group showed greater double support time/phase and stride width, and slower walking velocity, than the non-GD group. In an analysis of pooled data from all the subjects, gait-induced increases in cerebral perfusion were observed in the supplementary motor areas (SMA), lateral premotor cortex (PMC), primary motor and somatosensory areas, visual areas, basal ganglia and cerebellum. A between-group comparison of gait-induced perfusion changes showed relative underactivation of the SMA, thalamus and basal ganglia, together with relative overactivation of the PMC, in the GD group compared with the non-GD group. In a separate correlation analysis including all the subjects, as the double support phase was longer (that was, gait disturbance was more severe), the gait-induced perfusion changes were proportionally reduced in the SMA, visual cortex, and thalamus. The present study suggests that abnormalities in the basal ganglia-thalamo-cortical loops partly explain gait disturbance observed in a subset of subjects with ARWMC.

Impairment of the cortical GABAergic inhibitory system in catatonic stupor: a case report with neuroimaging.

We report the case of a 32-year-old patient who presented with catatonic stupor during the course of acute aseptic encephalitis involving the right frontotemporal area. Flumazenil-PET performed during the stupor indicated decreased benzodiazepine receptor binding in the right frontotemporal area where glucose metabolism was preserved as revealed by FDG-PET. An injection of diazepam immediately ameliorated catatonic symptoms and reduced widespread high amplitude slow EEG activities with right frontotemporal predominance. Compared with a SPECT study performed a week earlier, there was no abnormal right-sided anteriorly predominant cerebral hyperperfusion after injection of diazepam. While neither flumazenil- nor FDG-PET could be repeated, and with the caveat that generalized convulsions occurred initially and epilepsia partialis continua was present for two weeks starting on the 23rd day after illness onset, these findings suggest that in our case the presentation with catatonic stupor may be related to impairment of the cortical GABAergic inhibitory system.

Neural mechanisms involved in mental imagery and observation of gait.

Brain activity during observation and imagery of gait was investigated. Sixteen subjects were scanned with a 3-Tesla MRI scanner while viewing six types of video clips: observation of gait movement (GO) from the third-person perspective, observation of stepping movement, observation of standing posture, "virtual walking" (VW) that was observation of visual scenes mimicking the visual afferent during walking, and the scrambled version of the GO and VW stimuli. In the VW condition, moving scenes provided a virtual visual environment in which subjects easily imagined as if they were actually walking from the first-person perspective. A behavioral experiment revealed a correlation of cadence during actual walking with that during imaginary walking under the influence of the VW stimuli, indicating that a gait planning mechanism was shared by actual walking and gait imagery. The VW condition activated the dorsal premotor cortex (PMd), supplementary motor area/cingulate motor area (SMA/CMA), parahippocampal gyrus, and subcortical nuclei. The GO stimuli yielded activation of the SMA, PMd, inferior frontal gyrus, and inferior parietal lobule. Moreover, the conjunction null test of GO and VW revealed common activity in the SMA/CMA and PMd, which were reportedly active during actual gait movement, in addition to visual areas. Detailed analyses of activity during stepping or standing observation supported the specificity of the SMA and PMd to GO. These findings suggest that motor planning centers of gait, including the SMA and PMd, are activated during both imagination (first-person perspective) and observation (third-person perspective) of gait behaviors.