Symptoms Of Movement Disorders Research Articles

A tablet- and mobile-based application for remote diagnosis and analysis of movement disorder symptoms.

One significant hindrance to effective diagnosis of movement disorders (MDs) and analysis of their progression is the requirement for patients to conduct tests in the presence of a clinician. Here is presented a pilot study for diagnosis of essential tremor (ET), the world's most common MD, through analysis of a tablet- or mobile-based drawing task that may be selected at will, with the spiral- and line-drawing tasks of the Fahn-Tolosa-Marin tremor rating scale serving as our task in this work. This system replaces the need for pen-and-paper drawing tests while permitting advanced quantitative analysis of drawing smoothness, pressure applied, and other measures. Data is securely recorded and stored in the cloud, from which all analysis was conducted remotely. This will enable longitudinal analysis of patient disease progression without the need for excessive clinical visits. Several features were extracted and recursive feature elimination applied to rank the features' individual contribution to our classifier. Maximum cross-validated classification accuracy on a preliminary sample set was 98.3%. Future work will involve collecting healthy subject data from an age-controlled population and extending this diagnostic application to additional conditions, as well as incorporating regression-based symptom severity analysis. This highly promising new technology has the potential to substantially alleviate the demands placed on both clinicians and patients by bringing MD treatment more into line with the era of personalized medicine.

Non-motor symptoms in movement disorders: more than meets the eye.

This commentary is on the original article by Uchitel et al. on pages 820–826 of this issue.

Alzheimer’s Disease and Parkinson’s Disease: A Nutritional Toxicology Perspective of the Impact of Oxidative Stress, Mitochondrial Dysfunction, Nutrigenomics and Environmental Chemicals

Introduction: Alzheimer’s disease is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while Parkinson’s disease is primarily a movement disorder illness having movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. While aging is the main risk factor, epidemiological evidence suggests that the exposure to environmental toxicants, mainly pesticides, metals and solvents could increase the risk of developing neurodegenerative conditions.Oxidative stress in neurodegenerative diseases: Mitochondria function impacts cell respiratory processes, metabolism, energy production, intracellular signaling, free radical production, and apoptosis. In neurodegenerative diseases, mitochondrial dysfunction is associated with a compromised energy production, impaired calcium buffering, activation of proteases and phospholipases, and increased oxidative stress. Oxidative stress induced microglial cells activation, protein aggregation, neuroinflammation and mitochondrial dysfunction lead to neuronal deaths in these disorders.Role of nutrition: Neurodegenerative disease is not curable, but treatment is available to manage the symptoms and slow down the disease progression. The drugs for treating these diseases only reduce the cognitive impairment and behavioral problems, but do not stop the progression of neurodegeneration. Healthy diet, lifestyle improvement and nutraceuticals targeting of oxidative stress, inflammation, abnormal mitochondrial dynamics and the mitochondrial interaction with abnormal disease-related proteins and assessment of impact of environmental contaminants including occupational exposures to pesticides, can be a promising approach in the treatment of neurodegenerative diseases.Conclusion: These innovations can be benchmarked on firm understanding of nutrigenomics and the personalized management of individuals at risk.

Music Therapy and Music-Based Interventions for Movement Disorders.

There is emerging evidence that music therapy and other methods using music and rhythm may meaningfully improve a broad range of symptoms in neurological and non-neurological disorders. This review highlights the findings of recent studies utilizing music and rhythm-based interventions for gait impairment, other motor symptoms, and non-motor symptoms in Parkinson disease (PD) and other movement disorders. Limitations of current studies as well as future research directions are discussed. Multiple studies have demonstrated short-term benefits of rhythmic auditory stimulation on gait parameters including gait freezing in PD, with recent studies indicating that it may reduce falls. Demonstration of benefits for gait in both dopaminergic "on" and "off" states suggests that this intervention can be a valuable addition to the current armamentarium of PD therapies. There is also emerging evidence of motor and non-motor benefits from group dancing, singing, and instrumental music performance in PD. Preliminary evidence for music therapy and music-based interventions in movement disorders other than PD (such as Huntington disease, Tourette syndrome, and progressive supranuclear palsy) is limited but promising. Music therapy and other music and rhythm-based interventions may offer a range of symptomatic benefits to patients with PD and other movement disorders. Studies investigating the potential mechanisms of music's effects and well-controlled multicenter trials of these interventions are urgently needed.

Implantable Electronic Stimulation Devices from Head to Sacrum: Imaging Features and Functions.

Electronic stimulation devices are implanted in various locations in the body to decrease pain, modulate nerve function, or stimulate various end organs. The authors describe these devices using a craniocaudal approach, first describing deep brain stimulation (DBS) devices and ending with sacral nerve stimulation (SNS) devices. The radiology-relevant background information for each device and its imaging appearance are also described. These devices have a common design theme and include the following components: (a) a pulse generator that houses the battery and control electronics, (b) an insulated lead or wire that conveys signals to the last component, which is (c) an electrode that contacts the end organ and senses and/or acts on the end organ. DBS electrodes are inserted into various deep gray nuclei, most commonly to treat the symptoms of movement disorders. Occipital, trigeminal, and spinal nerve stimulation devices are used as second-line therapy to control craniofacial or back pain. For cardiac devices, the authors describe two newer devices, the subcutaneous implantable cardioverter defibrillator and the leadless pacemaker, both of which avoid complications related to having leads threaded through the venous system. Diaphragmatic stimulation devices stimulate the phrenic nerve to restore diaphragmatic movement. Gastric electrical stimulation devices act on various parts of the stomach for the treatment of gastroparesis or obesity. Finally, SNS devices are used to modulate urinary and defecatory functions. Common complications diagnosed at imaging include infection, hematoma, lead migration, and lead breakage. Understanding the components, normal function, and normal imaging appearance of each device allows the radiologist to identify complications. ©RSNA, 2019.

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders.

Acetylcholine (ACh) released from cholinergic interneurons acting through nicotinic and muscarinic acetylcholine receptors (mAChRs) in the striatum have been thought to be central for the potent cholinergic regulation of basal ganglia activity and motor behaviors. ACh activation of mAChRs has multiple actions to oppose dopamine (DA) release, signaling, and related motor behaviors and has led to the idea that a delicate balance of DA and mAChR signaling in the striatum is critical for maintaining normal motor function. Consistent with this, mAChR antagonists have efficacy in reducing motor symptoms in diseases where DA release or signaling is diminished, such as in Parkinson's disease and dystonia, but are limited in their utility because of severe adverse effects. Recent breakthroughs in understanding both the anatomical sites of action of ACh and the mAChR subtypes involved in regulating basal ganglia function reveal that the M4 subtype plays a central role in regulating DA signaling and release in the basal ganglia. These findings have raised the possibility that sources of ACh outside of the striatum can regulate motor activity and that M4 activity is a potent regulator of motor dysfunction. We discuss how M4 activity regulates DA release and signaling, the potential sources of ACh that can regulate M4 activity, and the implications of targeting M4 activity for the treatment of the motor symptoms in movement disorders. © 2019 International Parkinson and Movement Disorder Society.

Structural connectivity-based topography of the human globus pallidus: Implications for therapeutic targeting in movement disorders.

Understanding the topographical organization of the cortico-basal ganglia circuitry is of pivotal importance because of the spreading of techniques such as DBS and, more recently, MR-guided focused ultrasound for the treatment of movement disorders. A growing body of evidence has described both direct cortico- and dento-pallidal connections, although the topographical organization in vivo of these pathways in the human brain has never been reported. To investigate the topographical organization of cortico- and dento-pallidal pathways by means of diffusion MRI tractography and connectivity based parcellation. High-quality data from 100 healthy subjects from the Human Connectome Project repository were utilized. Constrained spherical deconvolution-based tractography was used to reconstruct structural cortico- and dento-pallidal connectivity. Connectivity-based parcellation was performed with a hypothesis-driven approach at three different levels: functional regions (limbic, associative, sensorimotor, and other), lobes, and gyral subareas. External globus pallidus segregated into a ventral associative cluster, a dorsal sensorimotor cluster, and a caudal "other" cluster on the base of its cortical connectivity. Dento-pallidal connections clustered only in the internal globus pallidus, where also associative and sensorimotor clusters were identified. Lobar parcellation revealed the presence in the external globus pallidus of dissociable clusters for each cortical lobe (frontal, parietal, temporal, and occipital), whereas in internal globus pallidus only frontal and parietal clusters were found out. We mapped the topographical organization of both internal and external globus pallidus according to cortical and cerebellar connections. These anatomical data could be useful in DBS, radiosurgery and MR-guided focused ultrasound targeting for treating motor and nonmotor symptoms in movement disorders. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Analysis of the prevalence and onset of dysphonia and dysphagia symptoms in movement disorders at an academic medical center

Voice and swallowing impairments are common in movement disorders, but their effect on patients’ quality of life is not well known. This study was conducted to determine the onset and prevalence of patient-reported dysphonia and dysphagia symptoms in Parkinson’s disease (PD), dystonia, Atypical Parkinsonian Syndromes (APS), and Essential Tremor (ET). Patients referred to a movement disorders clinic in a tertiary care academic medical center completed validated voice and swallowing specific Quality of Life (QOL) questionnaires: Voice Handicap Index-10 (VHI-10) and Eating Assessment Tool-10 (EAT-10). Patient demographics and clinical data were also collected. Two hundred and sixty-eight patients (males = 150, females = 118) completed the questionnaires (n was PD = 103, APS = 30, ET = 56, dystonia = 32, other = 47). Prevalence of patient-reported dysphagia symptoms was significantly higher in APS (63%) than PD (26%), ET (25%), and dystonia (31%). Prevalence of patient-reported dysphonia symptoms was significantly lower in ET (14%) compared to PD (34%) and APS (43%). Disease duration was shorter in PD and APS compared to ET and dystonia (p < 0.05) before reporting clinically significant dysphonia and dysphagia symptoms indicating an earlier onset of these symptoms. There were significant positive correlations between VHI-10 and EAT-10 scores and disease severity, as indicated by Unified Parkinson’s Disease motor scores (p < 0.0001) and modified Fahn-Tolosa-Marin Tremor Rating sub-scores (p = 0.0013). Patient-reported dysphonia and dysphagia symptoms were present in one fourth of patients with PD, ET, dystonia, and almost two thirds in APS. Patient-reported QOL measures, such as VHI-10 and EAT-10, can help screen movement disorder patients for dysphonia and dysphagia symptoms.

Design of Hidden-Property-Based Variable Universe Fuzzy Control for Movement Disorders and Its Efficient Reconfigurable Implementation

One of the challenging problems in real-time control of movement disorders is the effective handling of time-variant brain activities that involve stochastic functional networks with nonlinear dynamics. For such challenges in neuromodulation tasks, fuzzy logic control (FLC) has shown significant potential. The objective of this paper is to present a FLC-based strategy to treat pathological symptoms of movement-disorder with higher performance. The strategy is two-fold: first, develop a design methodology for the FLC system that can robustly control pathological conditions and significantly improve control performance; and second, develop a hardware-efficient implementation for real-time neuromodulation applications. To enhance control performance, a hidden variable in the neural network that can be estimated using an unscented Kalman filter is identified as a feedback variable. In comparison with state-of-the-art schemes, the proposed design can adaptively optimize the control signals without requiring particular information of the controlled plant, thus avoiding repeated determinations of controller parameters. A field-programmable gate array is used for the reconfigurable realization of the entire control strategy based on a modification of the original neural network. The presented design, with enhanced control performance and higher hardware efficiency, has significant potential for clinical treatment of movement disorders and offers a new perspective on applications in the fields of neural control engineering and brain–machine interfaces.

Patient-Specific Simulations of Deep Brain Stimulation Electric Field with Aid of In-house Software ELMA.

Deep brain stimulation (DBS) is an established technique for reduction of symptoms in movement disorders. Finite element method (FEM) simulations of the electric field magnitude (EF) are useful for estimating the affected tissue around the DBS lead and this can help optimize the therapy. This paper describes how patient-specific FEM models can be set up with the aid of the Matlab-based in-house software tool ELMA. Electrode placement is determined from two coordinates in postoperative medical imaging and electric conductivity is assigned from preoperative magnetic resonance imaging (MRI) and patient-specific DBS data. Simulations are performed using the equation for steady currents in Comsol Multiphysics (CM). The simulated EF is superimposed on the preoperative MRI for evaluation of affected structures. The method is demonstrated with patient-specific simulations in the zona incerta and a globus pallidus example containing cysts with higher conductive which causes considerable distortion of the EF. The improved software modules and precise lead positioning simplifies and reduces the time for DBS EF modelling and simulation.

Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.

Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders. In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse. In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies. Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington's disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson's disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future. Currently, there are no human studies that investigated the effects of CBD in either Alzheimer's disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies. Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.

WAKE: Wavelet decomposition coupled with adaptive Kalman filtering for pathological tremor extraction

Abstract Pathological Hand Tremor (PHT) is among common symptoms of several neurological movement disorders, which can significantly degrade quality of life of affected individuals. Beside pharmaceutical and surgical therapies, mechatronic technologies have been utilized to control PHTs. Most of these technologies function based on estimation, extraction, and characterization of tremor movement signals. Real-time extraction of tremor signal is of paramount importance because of its application in assistive and rehabilitative devices. In this paper, we propose a novel on-line adaptive method which can adjust the hyper-parameters of the filter to the variable characteristics of the tremor. The proposed Wavelet decomposition coupled with adaptive Kalman filtering technique for pathological tremor Extraction, referred to as the WAKE framework, is composed of a new adaptive Kalman filter and a wavelet transform core to provide indirect prediction of the tremor, one sample ahead of time, to be used for its suppression. In this paper, the design, implementation and evaluation of WAKE are given. The performance is evaluated based on three different datasets, the first one is a synthetic dataset, developed in this work, that simulates hand tremor under ten different conditions. The second and third ones are real datasets recorded from patients with PHTs. The results obtained from the proposed WAKE framework demonstrate significant improvements in the estimation accuracy in comparison with two well regarded techniques in the literature.

The prevalence of chronic low back pain and lumbar deformities in patients with Parkinson's disease: implications on spinal surgery.

This observational study was aimed at quantification of low back pain (LBP) in Parkinsonian patients and its morphological correlation. Parkinson's disease (PD) is a common disabling condition in the elderly population. Parkinsonian patients frequently are troubled by LBP. Causes for LBP in PD are muscular imbalances by the movement disorder itself and skeletal degeneration. Ninety-seven PD patients and 97 controls were inquired about low back pain through the Oswestry Low Back Pain Disability Questionnaire and visual analogue scales. Fifty-four patients with LBP underwent X-ray of the lumbar spine in two planes and flexion-extension views. Parkinson's disease was characterized by stage, disease duration, motor score, lateralization of symptoms and dosage of medication. LBP occurred significantly more frequent in PD (87.6%) compared to controls (62.6%) with longer duration and higher pain intensity. Pain intensity and disability scores were associated with higher PD stages and higher motor scores. Patients with the hypokinetic PD subtype experienced more pain intensity. X-ray of the lumbar spine revealed lumbar arthrosis in 79.6%, scoliosis in 38.8% and spondylolisthesis in 24.1% of PD patients with LBP. Lateralization of scoliosis and PD symptoms were significantly correlated. Only a small portion of PD patients with LBP received specialized orthopaedic treatment. LBP and lumbar degeneration are common in PD. Both are related to movement disorder symptoms. The knowledge about musculoskeletal conditions in Parkinson's disease is important for an interdisciplinary conservative or operative treatment decision of LBP. These slides can be retrieved under Electronic Supplementary Material.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

A case of factitious disorder presenting with symptoms of movement disorder

Factitious disorder (FD) is a diagnostic entity in which patients intentionally create false physical or mental symptoms. Although the disorder is rare, having an early diagnose is critical, becaus...

Hand Tremor Questionnaire: A Useful Screening Tool for Differentiating Patients with Hand Tremor between Parkinson's Disease and Essential Tremor.

Background and PurposeHand tremor is one of the most frequent symptoms in movement disorders, and differential diagnoses for hand tremor include Parkinson's disease (PD) and essential tremor (ET). However, accurately differentiating between PD and ET in clinical practice remains challenging in patients presenting with hand tremor. We investigated whether a questionnaire-based survey could be useful as a screening tool in patients with hand tremor.MethodsA questionnaire related to hand tremor consisting of 12 items was prospectively applied to patients with PD or ET in three movement-disorder clinics. Each question was analyzed, and a query-based scoring system was evaluated for differentiating hand tremors between PD and ET.ResultsThis study enrolled 24 patients with PD and 25 patients with ET. Nine of the 12 questions differed significantly between PD and ET: 1 about resting tremor, 4 questions about action tremor, and 4 about asymmetry. A receiver operating characteristics curve analysis revealed that the 9-item questionnaire showed a good discrimination ability, with a sensitivity of 88% and a specificity of 84%.ConclusionsThe developed Hand Tremor Questionnaire might be a good screening tool for hand tremors in patients with PD and ET.

Neues zur symptomatischen MS-Therapie: Teil 4 – Störungen der Sexualfunktion und der Augenbewegungen

The symptomatic treatment of multiple sclerosis (MS) is nowadays of similar importance as immunotherapy within acomprehensive treatment concept of this chronic disease. It makes a considerable contribution to the reduction of disabilities in activities of daily living as well as social and occupational life. Moreover, symptomatic treatment is of great importance for amelioration of the quality of life. Since our last survey of symptomatic MS treatment in 2004 and publication of the guidelines of the German Neurological Society and the Clinical Competence Network Multiple Sclerosis (Klinisches Kompetenznetz Multiple Sklerose, KKNMS) in 2014, several developments within the topics of mobility, bladder and sexual function, vision, fatigue, cognition and rehabilitation have taken place. These new findings together with further aspects of disease measurement methods and overall treatment strategies of the respective symptoms as well as treatment goals are introduced in several individual contributions. In this article the symptoms of sexual dysfunction and eye movement disorders are discussed.

Movement disorders caused by benign brain tumor

Background: Benign brain tumor can be manifested by movement disorders (MD). The clinical description and role of brain imaging in the diagnosis of a patient with MD symptoms is presented.

Transglucosidase improves the bowel movements in type 2 diabetes mellitus patients: A preliminary randomized double-blind, placebo-controlled study.

Recent studies have highlighted the relationship between gut microbiota and bowel movements. We aimed to evaluate transglucosidase treatment efficacy for bowel movements in patients with type 2 diabetes mellitus and to clarify the relationship between bowel movements, dietary habits, gut microbiota and fecal short-chain fatty acids. In this randomized double-blind, placebo-controlled study, 66 patients received placebo or transglucosidase (300 or 900 mg/day) orally, for 12 weeks. Fecal bacterial communities and short-chain fatty acids were analyzed before and after the treatment. Transglucosidase treatment significantly (p < 0.05) affected fecal microbiota (Prevotella spp., Bacteroides spp., Bifidobacterium spp., and Clostridium subcluster XIVa) and fecal short-chain fatty acid (acetate, valerate, succinate and lactate) content. Clostridium cluster IV, Clostridium subcluster XIVa, Clostridium cluster XVIII and fecal pH increased significantly and order Lactobacillales decreased in patients with bowel movement disorder compared with controls. Transglucosidase treatment significantly improved bowel movements compared with placebo treatment (46.2%, 95% confidence interval: 19.2-74.9% vs. 0%, 95% confidence interval: 0-33.6%, p < 0.05). This effect was not observed in patients without bowel movement disorder. Patients with bowel movement disorder suffer from gut dysbiosis. Transglucosidase treatment alleviates bowel movement disorder symptoms in type 2 diabetes mellitus patients by increasing fecal acetate level.

Environmental exposure to manganese in air: Tremor, motor and cognitive symptom profiles

BackgroundExcessive exposure to manganese (Mn) may cause parkinsonian-like motor and tremor symptoms and adverse cognitive effects, including problems with executive functioning (EF), resembling those found in later-stage Parkinson’s disease (PD). Studies seeking to differentiate PD patients into subgroups with associated cognitive and functional outcomes using motor and tremor symptoms identified tremor-dominant (TD) and non-tremor dominant (NTD) subtypes. It is unclear whether differing patterns of pathophysiology and symptoms exist in Mn neurotoxicity, as they do in PD. MethodsResidents of East Liverpool (n=83) and Marietta, OH (n=99) exposed to chronic (>10years) environmental Mn through industrial pollution were administered neuropsychological measures and a physician-rated scale of movement-disorder symptoms. Two-step cluster analysis was used to group residents based on tremor symptoms, bradykinesia/rigidity symptoms, gait disturbance, and executive function. Cluster membership was validated using modeled air-Mn exposure and a computerized tremor measure. ResultsElevated tremor and motor symptoms and executive dysfunction were observed, and TD and NTD symptom clusters were identified. Two additional clusters were also identified: Executive Dysfunction and Normal Functioning. The NTD residents, with elevated levels of gait disturbance and other movement disorder symptoms, did not evidence EF impairment, as predicted. Instead, residents with EF impairment formed their own cluster, and were relatively free of movement disorder symptoms. ConclusionsResults resemble reports in the PD literature with TD and NTD clusters identified, but executive dysfunction did not cluster with NTD symptoms. PD and Mn exposure likely have differing pathophysiology and developmental courses, and therefore different symptom patterns, even when similar symptoms are present.