Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Insula as the Interface Between Body Awareness and Movement: A Neurofeedback-Guided Kinesthetic Motor Imagery Study in Parkinson's Disease.

Intentional movement is an internally driven process that requires the integration of motivational and sensory cues with motor preparedness. In addition to the motor cortical-basal ganglia circuits, the limbic circuits are also involved in the integration of these cues. Individuals with Parkinson's disease (PD) have a particular difficulty with internally generating intentional movements and maintaining the speed, size, and vigor of movements. This difficulty improves when they are provided with external cues suggesting that there is a problem with the internal motivation of movement in PD. The prevailing view attributes this difficulty in PD to the dysfunction of motor cortical-basal ganglia circuits. First, we argue that the standard cortical-basal ganglia circuit model of motor dysfunction in PD needs to be expanded to include the insula which is a major hub within the limbic circuits. We propose a neural circuit model highlighting the interaction between the insula and dorsomedial frontal cortex which is involved in generating intentional movements. The insula processes a wide range of sensory signals arising from the body and integrates them with the emotional and motivational context. In doing so, it provides the impetus to the dorsomedial frontal cortex to initiate and sustain movement. Second, we present the results of our proof-of-concept experiment demonstrating that the functional connectivity of the insula-dorsomedial frontal cortex circuit can be enhanced with neurofeedback-guided kinesthetic motor imagery using functional magnetic resonance imaging in subjects with PD. Specifically, we found that the intensity and quality of body sensations evoked during motor imagery and the emotional and motivational context of motor imagery determined the direction (i.e., negative or positive) of the insula-dorsomedial frontal cortex functional connectivity. After 10-12 neurofeedback sessions and "off-line" practice of the successful motor imagery strategies all subjects showed a significant increase in the insula-dorsomedial frontal cortex functional connectivity. Finally, we discuss the implications of these results regarding motor function in patients with PD and propose suggestions for future studies.

Caffeine Consumption in First-Degree Relatives of Essential Tremor Cases: Evidence of Dietary Modification Before Disease Onset.

BACKGROUND: Caffeine can exacerbate tremor. Reducing caffeine intake or switching to decaffeinated beverages can lessen tremor. Unaffected relatives of essential tremor (ET) cases often have mild, subclinical tremor. One question is whether the coffee and tea consumption pattern in these individuals differs from that of controls (Co). METHODS: We ascertained the patterns of coffee and tea intake using a structured questionnaire, and compared the use in unaffected first-degree relatives of ET cases (FD-ET) to the use in age-matched Co. Three measures of relative caffeinated coffee + tea to decaffeinated coffee + tea were constructed. Caffeine index 1 = (cups of caffeinated coffee + tea) - (cups of decaffeinated coffee + tea) consumed on the day of evaluation. Caffeine index 2 = (cups of caffeinated coffee + tea) - (cups of decaffeinated coffee + tea) consumed in a typical month. The percentage of coffee and tea that was caffeinated in a typical month was also calculated. RESULTS: There were 263 individuals (190 FD-ET, 73 Co). Caffeine index 1 in FD-ET was less than 1-half that of Co (p = 0.001). Caffeine index 2 was similarly lower in FD-ET than Co (p = 0.027). The percentage of coffee and tea that was caffeinated in a typical month was also significantly lower in FD-ET than Co (p = 0.018). CONCLUSION: The balance of caffeinated to decaffeinated beverages is different in FD-ET than Co. These data raise several intriguing questions. Among these is whether relatives of ET cases modify their caffeine consumption before disease onset.

Decreased Coenzyme Q10 Levels in Multiple System Atrophy Cerebellum.

In familial and sporadic multiple system atrophy (MSA) patients, deficiency of coenzyme Q10 (CoQ10) has been associated with mutations in COQ2, which encodes the second enzyme in the CoQ10 biosynthetic pathway. Cerebellar ataxia is the most common presentation of CoQ10 deficiency, suggesting that the cerebellum might be selectively vulnerable to low levels of CoQ10 To investigate whether CoQ10 deficiency represents a common feature in the brains of MSA patients independent of the presence of COQ2 mutations, we studied CoQ10 levels in postmortem brains of 12 MSA, 9 Parkinson disease (PD), 9 essential tremor (ET) patients, and 12 controls. We also assessed mitochondrial respiratory chain enzyme activities, oxidative stress, mitochondrial mass, and levels of enzymes involved in CoQ biosynthesis. Our studies revealed CoQ10 deficiency in MSA cerebellum, which was associated with impaired CoQ biosynthesis and increased oxidative stress in the absence of COQ2 mutations. The levels of CoQ10 in the cerebella of ET and PD patients were comparable or higher than in controls. These findings suggest that CoQ10 deficiency may contribute to the pathogenesis of MSA. Because no disease modifying therapies are currently available, increasing CoQ10 levels by supplementation or upregulation of its biosynthesis may represent a novel treatment strategy for MSA patients.

Brain structural changes in essential tremor: voxel-based morphometry at 3-Tesla.

BACKGROUND: Abnormalities in cerebello-thalamo-cortical pathways have been suggested as a basis for essential tremor (ET). Two voxel-based morphometry (VBM) studies, each using a 1.5-T magnet, evaluated ET patients, leading to contradictory results. Using a 3-T magnet, we assessed whether white or gray matter changes occurred in ET patients vs. controls. METHODS: We recruited 19 ET patients (mean age 69.8+/-9.4 years) and 20 age and gender-matched controls. 3-T MRI data were analyzed using the Statistical Parametric Mapping (SPM) 5 package. RESULTS: In case-control comparisons, white matter changes were seen in several areas (right cerebellum, left medulla, right parietal lobe, and right limbic lobe); gray matter changes were seen in several areas as well (bilateral cerebellum, bilateral parietal lobes, right frontal lobe, and right insula) (p<0.001, uncorrected at a voxel level). Compared with controls, ET patients with severe tremor had white matter changes in the midbrain, both occipital lobes, and right frontal lobe, and gray matter changes bilaterally in the cerebellum (p<0.001, uncorrected at a voxel level). CONCLUSIONS: Structural white and gray abnormalities may be detected in ET patients using VBM and a high-field MRI scanner. Such changes may be related to the pathological substrates associated with this disease.

Blood harmane is correlated with cerebellar metabolism in essential tremor: a pilot study.

BACKGROUND: On proton magnetic resonance spectroscopic imaging ((1)H MRSI), there is a decrease in cerebellar N-acetylaspartate/total creatine (NAA/tCr) in essential tremor (ET), signifying cerebellar neuronal dysfunction or degeneration. Harmane, which is present in the human diet, is a potent tremor-producing neurotoxin. Blood harmane concentrations seem to be elevated in ET. OBJECTIVES: To assess in patients with ET whether blood harmane concentration is correlated with cerebellar NAA/tCR, a neuroimaging measure of neuronal dysfunction or degeneration. METHODS: Twelve patients with ET underwent (1)H MRSI. The major neuroanatomic structure of interest was the cerebellar cortex. Secondary regions were the central cerebellar white matter, cerebellar vermis, thalamus, and basal ganglia. Blood concentrations of harmane and another neurotoxin, lead, were also assessed. RESULTS: Mean +/- SD cerebellar NAA/tCR was 1.52 +/- 0.41. In a linear regression model that adjusted for age and gender, log blood harmane concentration was a predictor of cerebellar NAA/tCR (beta = -0.41, p = 0.009); every 1 g(-10)/mL unit increase in log blood harmane concentration was associated with a 0.41 unit decrease in cerebellar NAA/tCR. The association between blood harmane concentration and brain NAA/tCR only occurred in the cerebellar cortex; it was not observed in secondary brain regions of interest. Furthermore, the association was specific to harmane and not another neurotoxin, lead. CONCLUSION: This study provides additional support for the emerging link between harmane, a neurotoxin, and ET. Further studies are warranted to address whether cerebellar harmane concentrations are associated with cerebellar pathology in postmortem studies of the ET brain.

Impaired motor imagery in patients with essential tremor: a case control study.

Motor imagery (MI), which refers to the process of mental representation of movements, has not been studied in patients with essential tremor (ET). We investigated the presence of impaired MI in ET patients compared with healthy controls. A group of drug-naive and nondemented ET patients and age-matched controls were studied using transcranial magnetic stimulation, while they were specifically instructed to try and imagine themselves performing two motor tasks. The various clinical and electrophysiological variables were evaluated and compared. Repeated measures ANOVA demonstrated a significant difference between ET patients and controls with respect to mean motor-evoked potential (MEP) amplitudes (F(1,38) = 31.92, P < 0.005) during MI. The process of MI effectively facilitated MEP amplitude in controls but not in ET patients, regardless of side of stimulation or motor tasks. We provide evidence to demonstrate impairment of MI in a group of ET patients compared with healthy controls. The basis for this novel finding is unclear, and further studies are warranted to determine whether it is related to cerebellar or motor cortical dysfunction.

Semiquantitative study of current coffee, caffeine, and ethanol intake in essential tremor cases and controls.

There are several reasons to study caffeine, coffee, and ethanol intake in essential tremor (ET) patients. ET patients also might modify their use of these beverages because of their effects on tremor. Intake of caffeine, coffee, and ethanol has not been quantified in a group of ET patients. Our objective is to use a semiquantitative food frequency questionnaire to compare current daily intake of coffee, caffeine, and ethanol in ET patients and controls. A total of 130 ET cases were patients at the Neurological Institute of New York, and 175 controls were ascertained by random digit dialing. Caffeine (in milligrams) and ethanol (in grams) intake were calculated from a semiquantitative food-frequency questionnaire. Mean daily caffeine intake in patients was 138.4 versus 246.6 mg in controls; medians were 101.1 versus 175.5 mg (P < 0.001). Mean daily ethanol intake in patients was 8.2 versus 6.2 gm in controls; medians were 2.4 versus 1.9 gm (P = 0.89). Cases drank less coffee than controls, but drank similar amounts of tea, soft drinks, fruit juices, and milk. Daily caffeine intake was not correlated with tremor severity or duration. ET patients consumed less caffeine than did controls, which is likely to be a dietary modification in response to tremor. The observation that caffeine consumption was not correlated with tremor severity raises the additional possibility that lower caffeine consumption in ET patients may not exclusively be a response to tremor. A prospective study is needed to explore whether decreased caffeine consumption is a risk factor for ET.

Parkinsonian signs in older people: prevalence and associations with smoking and coffee.

BACKGROUND: Cigarette smoking and coffee consumption may reduce the risk of PD. Parkinsonian signs (tremor, rigidity, bradykinesia) occur in 30 to 40% of the elderly. OBJECTIVE: To determine whether there was an association between cigarette smoking, coffee consumption, and parkinsonian signs in a community population of older people. METHODS: Data on smoking were collected and a neurologic examination performed on 1,339 residents > or = 65 years of age in the Washington Heights-Inwood community in northern Manhattan, NY. Parkinsonian signs were rated with an abbreviated Unified Parkinson's Disease Rating Scale, resulting in a parkinsonian sign score. Coffee consumption was assessed with a semiquantitative food-frequency questionnaire, and caffeine consumption was determined. Analyses were cross-sectional. RESULTS: Mean age was 76.6 years. Parkinsonian signs were present in 537 (40.1%). The odds for presence of parkinsonian signs was lower in smokers than nonsmokers (odds ratio [OR] = 0.58, 95% CI = 0.47 to 0.73). Smokers had a lower mean parkinsonian sign score than nonsmokers (p < 0.001). Coffee drinking and caffeine consumption were not associated with the presence of parkinsonian signs. The odds for presence of parkinsonian signs remained lower in smokers (OR = 0.75, 95% CI = 0.57 to 0.99) after adjusting for age, gender, ethnicity, years of education, adjusted daily caffeine consumption, and dementia. CONCLUSION: The reduced risk of parkinsonian signs in cigarette smokers could reflect a protective effect of smoking on age-related parkinsonian signs in the elderly or an aversion to smoking in elderly persons with mild parkinsonism.