Balancing short-term symptom control and long-term functional outcomes in patients with Parkinson's disease

Levodopa has played a central role in the treatment of Parkinson's disease for nearly 40 years and remains the single most effective symptomatic treatment for the disease. However, the response to levodopa therapy changes over time, and its long-term use is commonly associated with disabling motor complications. For this reason, the appropriate role of levodopa in the treatment of Parkinson's disease-in particular, the question of when to initiate therapy with the drug-has been a matter of controversy. Because levodopa is the most effective treatment for Parkinson's disease, the management of this disease becomes a matter of balancing short-term symptom control with long-term functional outcomes. This article provides an overview of the basis for levodopa-associated motor complications and their impact on patients' clinical function and quality of life, followed by a discussion of strategies for managing these complications to achieve optimum symptom control while minimizing the adverse effects of long-term therapy.     

What catatonia can tell us about "top-down modulation": a neuropsychiatric hypothesis

Differential diagnosis of motor symptoms, for example, akinesia, may be difficult in clinical neuropsychiatry. Symptoms may be either of neurologic origin, for example, Parkinson's disease, or of psychiatric origin, for example, catatonia, leading to a so-called "conflict of paradigms." Despite their different origins, symptoms may appear more or less clinically similar. Possibility of dissociation between origin and clinical appearance may reflect functional brain organisation in general, and cortical-cortical/subcortical relations in particular. It is therefore hypothesized that similarities and differences between Parkinson's disease and catatonia may be accounted for by distinct kinds of modulation between cortico-cortical and cortico-subcortical relations. Catatonia can be characterized by concurrent motor, emotional, and behavioural symptoms. The different symptoms may be accounted for by dysfunction in orbitofrontal-prefrontal/parietal cortical connectivity reflecting "horizontal modulation" of cortico-cortical relation. Furthermore, alteration in "top-down modulation" reflecting "vertical modulation" of caudate and other basal ganglia by GABA-ergic mediated orbitofrontal cortical deficits may account for motor symptoms in catatonia. Parkinson's disease, in contrast, can be characterized by predominant motor symptoms. Motor symptoms may be accounted for by altered "bottom-up modulation" between dopaminergic mediated deficits in striatum and premotor/motor cortex. Clinical similarities between Parkinson's disease and catatonia with respect to akinesia may be related with involvement of the basal ganglia in both disorders. Clinical differences with respect to emotional and behavioural symptoms may be related with involvement of different cortical areas, that is, orbitofrontal/parietal and premotor/motor cortex implying distinct kinds of modulation--"vertical" and "horizontal" modulation, respectively.     

The effects of nicotine on Parkinson's disease

Post-mortem studies have demonstrated a substantial loss of nicotinic receptors in Parkinson's disease (PD), which may be at least partially responsible for some of the cognitive, motoric, and behavioral deficits seen in this disorder. Epidemiologic studies have suggested that cigarette smoking is a strong negative risk factor for the development of PD. We have previously shown that blockade of central nicotinic receptors produces cognitive impairment in areas of new learning, short-term memory, and psychomotor slowing with increasing dose sensitivity with age and disease. Studies of acute stimulation of nicotinic receptors in Alzheimer's disease with nicotine and the novel agonist ABT-418 in our laboratory and others have shown improvements in several measures of cognitive function. Prior studies of the effects of nicotine in PD have suggested some improvements in clinical symptomatology. We have begun quantitative studies of both acute and chronic nicotine in PD to assess both cognitive and motor effects. Fifteen (15) nondemented subjects (age 66 +/- 5.3; M/F = 11/4) with early to moderate PD (mean Hoehn-Yahr stage = 1.77; MMSE = 28.6) received a dose-ranging study of intravenous nicotine up to 1.25 microg/kg/min, followed by chronic administration of nicotine by transdermal patch with doses ranging up to 14 mg per day for 2 weeks. Testing occurred both during drug administration and up to 2 months after drug cessation to look for prolonged effects. Preliminary analysis shows improvements after acute nicotine in several areas of cognitive performance, particularly measures such as reaction time, central processing speed, and decreased tracking error. Improvements in attention and semantic retrieval were not seen. After chronic nicotine, improvements were seen in several motor measures suggesting improved extrapyramidal functioning. This appeared to be sustained for up to 1 month after drug. The treatment was well tolerated. Nicotinic stimulation may have promise for improving both cognitive and motor aspects of Parkinson's disease.     

Articulatory consequences of Parkinson's disease: perspectives from two modalities.

Language production involves complex yet productively varying motor behavior. Rule-governed combinations yield a finite set of formational units combined in an infinite number of ways. The creativity of language ensures that no particular articulation will be highly automatized. Linguistic articulation is highly complex and varied. As such, it differs from the other more automatized motor behaviors typically studied such as learned movements in apraxia studies or repetitive behavior as occurs in walking or other everyday activities. Language also strives to maintain a balance between ease of articulation and ease of perception, while maintaining linguistically relevant distinctions. We report here a number of studies on the articulatory consequences of Parkinson's disease (PD) in the spoken and signed modalities. Our goal is to highlight the commonalities and distinctions between the two modalities of speech and sign that will allow us to better understand the impingements of PD on language production in general.     

Impulse-control disorders in Parkinson's disease

Parkinson's disease is a neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, and resting tremor. Increasingly, Parkinson's disease has been associated with a broad spectrum of non-motor symptoms, such as olfactory loss, sleep disorders, autonomic dysfunction, cognitive impairment, psychosis, depression, anxiety, and apathy. In addition, a minority of Parkinson's disease patients develop compulsive behaviors while receiving dopamine-replacement therapy, including medication hoarding, pathological gambling, binge eating, hyperlibidinous behavior, compulsive shopping, and punding. These behaviors may result in psychosocial impairment for patients and therapeutic challenges for clinicians. This article reviews the anatomic substrates, behavioral spectrum, associated factors, and potential treatments for dopamine-replacement therapy-related compulsions in Parkinson's disease.     

Emotional dysfunction in Parkinson's disease

In addition to motor symptomatology, idiopathic Parkinson's disease is characterized by emotional dysfunction. Depression affects some 30 to 40 percent of Parkinson patients and other psychiatric co-morbidities include anxiety and apathy. Neuropsychological and neuroimaging studies of emotional dysfunction in Parkinson patients suggest abnormalities involving mesolimbic and mesocortical dopaminergic pathways. There is also evidence suggesting that the interaction between serotonin and dopamine systems is important in the understanding and treatment of mood disorders in Parkinson's disease. In this review we discuss the neuropsychiatric abnormalities that accompany Parkinson's disease and describe their neuropsychological, neuropharmacologic, and neuroimaging concomitants.     

Maternal separation exaggerates the toxic effects of 6-hydroxydopamine in rats: implications for neurodegenerative disorders

Many studies have shown that early life stress may lead to impaired brain development, and may be a risk factor for developing psychiatric pathologies such as depression. However, few studies have investigated the impact that early life stress might have on the onset and development of neurodegenerative disorders, such as Parkinson's disease, which is characterized in part by the degeneration of dopaminergic neurons in the nigrostriatal pathway. The present study subjected rat pups to a maternal separation paradigm that has been shown to model adverse early life events, and investigated the effects that it has on motor deficits induced by a unilateral, intrastriatal injection of 6-hydroxydopamine (12 microg/4 microl). The female rats were assessed for behavioral changes at 28 days post-lesion with a battery of tests that are sensitive to the degree of dopamine loss. The results showed that rats that had been subjected to maternal separation display significantly impaired performance in the vibrissae and single-limb akinesia test when compared to normally reared animals. In addition, there was a significant increase in the loss of tyrosine hydroxylase staining in maternally separated rats. Our results therefore suggest that adverse experiences sustained during early life contribute to making dopamine neurons more susceptible to subsequent insults occurring during more mature stages of life and may therefore play a role in the etiopathogenesis of Parkinson's disease.     

A characterization of the prosodic loss in Parkinson's disease

Prosodic contours in the verbal output of 30 patients with Idiopathic Parkinson's disease were contrasted to those of fifteen age-, sex-, and educationally matched normal subjects. All subjects were tested for language disorder, dementia, depression, and the comprehension of linguistic prosody. The striking disorder of prosody in Parkinson's disease relates to motor control, not to a loss of the linguistic knowledge required to make prosodic distinctions. It appears that prosody, language and the motor planning of speech are integrated at a basal ganglia level.     

Neuropsychological aspects of Parkinson's disease

The neuropsychological effects of Parkinson's disease have gained wide recognition in recent literature. Effects have been documented in almost all areas of cognitive functioning, including general intellectual functioning, visual-spatial functioning, executive functions, attention and memory functions, language functions, and affective processes. Visual-spatial functions, memory functions, and executive functions have received particular interest. This review of the literature is an attempt to tie together the large number of studies in these cognitive areas and to present a suggestion for a comprehensive neuropsychological battery tailored to the patient with Parkinson's disease. Throughout the review, factors relevant to Parkinson's disease, e.g., dementia, motor symptoms, and hemiparkinsonism, are considered.     

Indications for the Use of Atypical Antipsychotics in the Elderly

There has been an expanding role for the new generation atypical antipsychotic agents (clozapine, risperidone, olanzapine, and quetiapine) in elderly patients. Their efficacy in the treatment of psychoses associated with schizophrenia is now well established. But psychoses occur in other conditions. This paper will review the current research examining the use of the atypical agents in the treatment of psychoses in the elderly in three somewhat overlapping conditions: schizophrenia, dementia, and Parkinson's disease, as well as in the amelioration of a variety of movement disorders. In the elderly, any of the atypicals can be used to treat schizophrenia, although clozapine may be a second line agent because of its side effect profile. Risperidone may be the drug of choice for the treatment of psychoses and behavioral disturbances in dementia. Clozapine is a primary choice and quetiapine an alternative for the treatment of psychoses in Parkinson's disease; while clozapine and possibly risperidone may be preferred for the initial treatment of some movement disorders. The differential effectiveness of these agents across treatment indications may, in part, be related to their differing affinities at several neurotransmitter receptors. Examination of these relationships in large scale longitudinal studies may help in the development of effective tailored treatments for the elderly.     

Age-related accelerated tapping response in healthy population

Different types of rapid tapping responses were described in the finger-tapping test. The "Hastening phenomenon" was described as an abnormal motor response in patients with Parkinson's disease. Accelerated tapping has been shown in a healthy elderly sample. It is not clear whether accelerated tapping relates to the hastening phenomenon or characterizes normal aging. We hypothesized that this sample of 21 healthy elderly people showed increased accelerated tapping but not hastening phenomenon. To assess this hypothesis, 20 healthy young and 21 elderly subjects performed a tapping test, requiring responses from 1 to 6 Hz. The healthy elderly sample showed increased accelerated tapping but not increased "hastening phenomenon." We conclude that Accelerated tapping may represent age-related motor processes unlike the hastening phenomenon characterizing Parkinson's disease.     

Parkinsonian speech disfluencies: effects of L-dopa-related fluctuations

The excess dopamine theory of stuttering (Wu et al., 1997) contends that stuttering may be related to excess levels of the neurotransmitter dopamine in the brain. As Parkinson's disease (PD) patients commonly exhibit changes in dopamine levels accompanied by changes in motor performance, the present study examined disfluency in PD patients to gain information on the role of dopamine in speech disfluencies. Nine PD patients with no history of developmental stuttering were recorded once before and twice after taking their morning medication (on separate days). They read a passage and produced a monologue. Within-word and overall speech disfluencies were calculated at each recording. Through motor testing, it was inferred that participants had relatively low dopamine levels before taking medication, and relatively high dopamine levels after taking medication. There were no group changes in disfluency levels when the low-dopamine and high-dopamine states were compared. There were, however, significant differences in percent disfluencies between the PD participants and age-matched controls. The results of this study do not strongly support the excess dopamine theory of stuttering. Rather, the disfluency changes exhibited by individual participants support a hypothesis that speech disfluencies may be related to increases or decreases in dopamine levels in the brain. EDUCATIONAL OBJECTIVES: The reader will learn about: (1). the characteristics of disfluent speech exhibited by speakers with Parkinson's disease. (2). The effect of L-dopa based medications on disfluencies of Parkinsonian speakers. (3). The complex role brain dopamine levels may play in disfluent speaking behavior.     

Motor sequence learning performance in Parkinson's disease patients depends on the stage of disease

It is still unclear, whether patients with Parkinson's disease (PD) are impaired in the incidental learning of different motor sequences in short succession, although such a deficit might greatly impact their daily life. The aim of this study was thus to clarify the relation between disease parameters of PD and incidental motor learning of two different sequences in short succession. Results revealed that the PD patients were able to acquire two sequences in short succession but needed more time than healthy subjects. However, both the severity of axial manifestations, as assessed on a subsection of the Unified Parkinson's Disease Rating Scale III (UPDRS III) and the Hoehn and Yahr score, and the levodopa-equivalent dose (LED) were negatively correlated with the sequence learning performance. These findings indicate that, although PD patients are able to learn two sequences in short succession, they need more time and their overall sequence learning performance is strongly correlated with the stage of disease.     

Impact of Neurologic Deficits on Motor Imagery: A Systematic Review of Clinical Evaluations

Motor imagery (MI, the mental representation of an action without engaging in its actual execution) is a therapeutically relevant technique to promote motor recovery after neurologic disorders. MI shares common neural and psychological bases with physical practice. Interestingly, both acute and progressive neurologic disorders impact brain motor networks, hence potentially eliciting changes in MI capacities. How experimental neuroscientists and medical practitioners should assess and take into account these changes in order to design fruitful interventions is largely unresolved. Understanding how the psychometric, behavioral and neurophysiological correlates of MI are impacted by neurologic disorders is required. To address this brain-behavior issue, we conducted a systematic review of MI data in stroke, Parkinson’s disease, spinal cord injury, and amputee participants. MI evaluation methods are presented. Redundant MI profiles, primarily based on psychometric and behavioral evaluations, emerged in each clinical population. When present, changes in the psychometric and behavioral correlates of MI were highly congruent with the corresponding motor impairments. Neurophysiological recordings yielded specific changes in cerebral activations during MI, which mirrored structural and functional reorganizations due to neuroplasticity. In this view, MI capacities may not be deteriorated per se by neurologic diseases resulting in chronic motor incapacities, but adjusted to the current state of the motor system. Literature-driven orientations for future clinical research are provided.     

Processing emotional tone from speech in Parkinson’s disease: A role for the basal ganglia

In this study, individuals with Parkinson's disease were tested as a model for basal ganglia dysfunction to infer how these structures contribute to the processing of emotional speech tone (emotional prosody). Nondemented individuals with and without Parkinson's disease (n = 21/group) completed neuropsychological tests and tasks that required them to process the meaning of emotional prosody in various ways (discrimination, identification, emotional feature rating). Individuals with basal ganglia disease exhibited abnormally reduced sensitivity to the emotional significance of prosody in a range of contexts, a deficit that could not be attributed to changes in mood, emotional-symbolic processing, or estimated frontal lobe cognitive resource limitations in most conditions. On the basis of these and broader findings in the literature, it is argued that the basal ganglia provide a critical mechanism for reinforcing the behavioral significance of prosodic patterns and other temporal representations derived from cue sequences (Lieberman, 2000), facilitating cortical elaboration of these events.     

Could an autonomous syntax module have evolved?

Darwinian evolution necessitates a contribution to reproductive fitness. Recent studies of aphasia and Parkinson's disease show that functional syntactic ability involves neural structures that also are involved in speech motor control and nonlinguistic cognition. The evolution or presence of an autonomous syntax module is, therefore, implausible.     

Presurgical Coping, Depression, and Quality of Life in Persons with Parkinson's Disease

This study describes utilization of coping strategies and evaluates the interaction between coping strategies, depression, and quality of life (QOL) in patients with Parkinson's disease (PD) who are being considered for neurosurgical intervention. Eighty patients (mean age 61.7 years) with PD being evaluated for possible deep brain stimulation completed self-report instruments of coping strategies (Coping Responses Inventory), depression (Beck Depression Inventory), and disease-specific QOL (Parkinson's Disease Questionnaire-39). Analyses showed that patients with PD cope with the acute stressor of approaching neurosurgery through a variety of strategies, but particularly avoidant and behavioral strategies. When the correlated but apparently opposing effects of cognitive and behavioral strategies were teased apart, greater use of cognitive strategies was associated with more severe depressive symptomatology (and poorer QOL), while greater use of behavioral strategies appeared to be associated with less depression. Depressive symptomatology, in turn, was associated with poorer QOL. However, coping had minimal direct association with QOL. From this it was concluded that patients with advanced PD generate a variety of coping responses to an acute stressor such as surgery, and the use of behavioral strategies, in particular seeking of alternative enjoyable activities, may be associated with better mood if salutary effects are not overwhelmed by less helpful cognitive coping techniques. The minimization of depressive symptomatology, in turn, is associated with better QOL.     

时间知觉的脑机制:时钟模型的困境和新导向

长期以来人们认为神经系统是通过类似于时钟的方式来实现对一段时间的知觉的,并认为多巴胺能系统(基地神经节)和时钟的快慢有关。与多巴胺信号有关的药物的动物实验的结果以及帕金森氏症(parkinson’s disease)患者的行为表现被看作是支持以上看法的证据。然而,最近的大量研究对这个理论提出了挑战,结合行为研究和脑机制研究的新成果,研究者提出了知觉信息可以通过神经活动状态或加工中的能量消耗来表达。     

Effect of speech task on intelligibility in dysarthria: a case study of Parkinson's disease

This study assessed intelligibility in a dysarthric patient with Parkinson's disease (PD) across five speech production tasks: spontaneous speech, repetition, reading, repeated singing, and spontaneous singing, using the same phrases for all but spontaneous singing. The results show that this speaker was significantly less intelligible when speaking spontaneously than in the other tasks. Acoustic analysis suggested that relative intensity and word duration were not independently linked to intelligibility, but dysfluencies (from perceptual analysis) and articulatory/resonance patterns (from acoustic records) were related to intelligibility in predictable ways. These data indicate that speech production task may be an important variable to consider during the evaluation of dysarthria. As speech production efficiency was found to vary with task in a patient with Parkinson's disease, these results can be related to recent models of basal ganglia function in motor performance.     

A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes

Attention-deficit/hyperactivity disorder (ADHD) is currently defined as a cognitive/behavioral developmental disorder where all clinical criteria are behavioral. Inattentiveness, overactivity, and impulsiveness are presently regarded as the main clinical symptoms. The dynamic developmental behavioral theory is based on the hypothesis that altered dopaminergic function plays a pivotal role by failing to modulate nondopaminergic (primarily glutamate and GABA) signal transmission appropriately. A hypofunctioning mesolimbic dopamine branch produces altered reinforcement of behavior and deficient extinction of previously reinforced behavior. This gives rise to delay aversion, development of hyperactivity in novel situations, impulsiveness, deficient sustained attention, increased behavioral variability, and failure to "inhibit" responses ("disinhibition"). A hypofunctioning mesocortical dopamine branch will cause attention response deficiencies (deficient orienting responses, impaired saccadic eye movements, and poorer attention responses toward a target) and poor behavioral planning (poor executive functions). A hypofunctioning nigrostriatal dopamine branch will cause impaired modulation of motor functions and deficient nondeclarative habit learning and memory. These impairments will give rise to apparent developmental delay, clumsiness, neurological "soft signs," and a "failure to inhibit" responses when quick reactions are required. Hypofunctioning dopamine branches represent the main individual predispositions in the present theory. The theory predicts that behavior and symptoms in ADHD result from the interplay between individual predispositions and the surroundings. The exact ADHD symptoms at a particular time in life will vary and be influenced by factors having positive or negative effects on symptom development. Altered or deficient learning and motor functions will produce special needs for optimal parenting and societal styles. Medication will to some degree normalize the underlying dopamine dysfunction and reduce the special needs of these children. The theory describes how individual predispositions interact with these conditions to produce behavioral, emotional, and cognitive effects that can turn into relatively stable behavioral patterns.