Pathophysiology of somatosensory abnormalities in Parkinson disease
TL;DR: It is argued that abnormal spatial and temporal processing of sensory information produces incorrect signals for the preparation and execution of voluntary movement and is likely to be a consequence of the dopaminergic denervation of the basal ganglia that is the hallmark of PD.
Abstract: Changes in sensory function that have been described in patients with Parkinson disease (PD) can be either 'pure' disorders of conscious perception such as elevations in sensory threshold, or disorders of sensorimotor integration, in which the interaction between sensory input and motor output is altered. In this article, we review the extensive evidence for disrupted tactile, nociceptive, thermal and proprioceptive sensations in PD, as well as the influences exerted on these sensations by dopaminergic therapy and deep brain stimulation. We argue that abnormal spatial and temporal processing of sensory information produces incorrect signals for the preparation and execution of voluntary movement. Sensory deficits are likely to be a consequence of the dopaminergic denervation of the basal ganglia that is the hallmark of PD. A possible mechanism to account for somatosensory deficits is one in which disease-related dopaminergic denervation leads to a loss of response specificity, resulting in transmission of noisier and less-differentiated information to cortical regions. Changes in pain perception might have a different explanation, possibly involving disease-related effects outside the basal ganglia, including involvement of peripheral pain receptors, as well as structures such as the periaqueductal grey matter and non-dopaminergic neurotransmitter systems.
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TL;DR: There is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions.
Abstract: Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.
302 citations
TL;DR: A review of the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of Parkinson's disease can be found in this article, where the authors focus on classical notions and recent insights.
Abstract: Cardinal motor features of Parkinson's disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.
217 citations
Cites background from "Pathophysiology of somatosensory ab..."
...Abnormalities of cortical excitability [64, 65], somatosensory function [66], and sensorimotor integration [67, 68] and changes in the pattern of activation in the motor and premotor cortices and the supplementary motor area [69, 70] may also contribute to deficits in movement execution in PD [47]....
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TL;DR: Patients develop a range of l‐dopa–induced complications that include motor and non‐motor symptoms, particularly fluctuations in neuropsychiatric, autonomic, and sensory symptoms.
Abstract: The first years of Parkinson disease (PD) treatment are marked by good and sustained responses to dopaminergic therapy. With disease progression and longer exposure to levodopa (l-dopa), patients develop a range of l-dopa-induced complications that include motor and non-motor symptoms. Motor complications include motor fluctuations, characterized by periods of reduced benefit from the medication, and l-dopa-induced dyskinesia, characterized by emergence of hyperkinetic involuntary movements. Dyskinesia can occur at peak effect of l-dopa, at the beginning and end of dose, or between doses. These motor complications are often associated with fluctuations in non-motor symptoms, particularly fluctuations in neuropsychiatric, autonomic, and sensory symptoms. Recognizing such complications and understanding their relationship with the timing of l-dopa doses is essential for adequate diagnosis and management. Society.
189 citations
Cites background from "Pathophysiology of somatosensory ab..."
...This suggests that these symptoms may be secondary to peripheral mechanisms associated with sustained muscle contraction in off-dystonia, rigidity, or musculoskeletal problems, as well as with primary somatosensory mechanisms.(117) Sensory symptoms are more frequent in the legs than the arms, with the neck and face being rarely affected....
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TL;DR: A review of the changes in neural circuitry and molecular signaling pathways that may underlie this complex relationship between pain and depression is performed.
Abstract: Acute pain induces depressed mood, and chronic pain is known to cause depression. Depression, meanwhile, can also adversely affect pain behaviors ranging from symptomology to treatment response. Pain and depression independently induce long-term plasticity in the central nervous system (CNS). Comorbid conditions, however, have distinct patterns of neural activation. We performed a review of the changes in neural circuitry and molecular signaling pathways that may underlie this complex relationship between pain and depression. We also discussed some of the current and future therapies that are based on this understanding of the CNS plasticity that occurs with pain and depression.
181 citations
Cites background from "Pathophysiology of somatosensory ab..."
...Interestingly, Parkinson’s disease, which presents a classic hypodopaminergic state, is associated with increased incidence of both depression and chronic pain [135, 136]....
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TL;DR: Results demonstrate that phasic LC activity enhances cortical encoding of salient stimuli by facilitating long-latency signals within target regions in response to stimulus intensity/salience.
Abstract: Phasic activation of locus coeruleus (LC)-norepinephrine (NE) neurons is associated with focused attention and behavioral responses to salient stimuli We used cell-type-specific optogenetics and single-unit neurophysiology to identify how LC activity influences neural encoding of sensory information We found that phasic, but not tonic, LC-NE photoactivation generated a distinct event-related potential (ERP) across cortical regions Salient sensory stimuli (which innately trigger phasic LC activity) produced strong excitatory cortical responses during this ERP window Application of weaker, nonsalient stimuli produced limited responses, but these responses were elevated to salient stimulus levels when they were temporally locked with phasic LC photoactivation These results demonstrate that phasic LC activity enhances cortical encoding of salient stimuli by facilitating long-latency signals within target regions in response to stimulus intensity/salience The LC-driven salience signal identified here provides a measure of phasic LC activity that can be used to investigate the LC's role in attentional processing across species
135 citations
Cites background from "Pathophysiology of somatosensory ab..."
...Furthermore, these findings predict that disorders in which LC-NE neurons are damaged or lost, such as Alzheimer’s disease or Parkinson’s disease, could result in impairment of sensory information processing and attentional gating, which are wellestablished deficits with such disorders (52)....
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References
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TL;DR: Electrical stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease and the severity of symptoms off medication decreases, and the dose of levodopa can be reduced with consequent reduction in dyskinesias.
Abstract: Background In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an “off” period (also referred to as “off medication”), when the medication is not working and the motor symptoms of parkinsonism are present, and an “on” period, when the medication is causing improved mobility (also referred to as “on medication”), often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease. Methods We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clin...
1,824 citations
TL;DR: The dopaminergic basis of the range of non-motor symptoms that occur in PD such as depression, apathy, sleep disorders (including rapid-eye movement sleep behaviour disorder), and erectile dysfunction are investigated.
Abstract: Several studies, including work from the Parkinson's disease (PD) non-motor group and others, have established that the non-motor symptoms of PD are common, occur across all stages of PD, are under-reported, and are a key determinant of quality of life. Research suggests that the non-motor symptoms of the disease are frequently unrecognised by clinicians and remain untreated. Even when identified, there is a common perception that many of these symptoms are untreatable. The role of dopaminergic drugs in treating the various non-motor problems of PD, although clinically recognised, has received little attention. In this Review, we investigate the dopaminergic basis of the range of non-motor symptoms that occur in PD such as depression, apathy, sleep disorders (including rapid-eye movement sleep behaviour disorder), and erectile dysfunction. We discuss the evidence that these symptoms are treatable, at least in part, with various dopaminergic strategies and, where relevant, we also refer to the use of deep-brain stimulation of appropriate targets in the brain. This Review provides a comprehensive overview of the management of this challenging aspect of PD.
1,456 citations
TL;DR: In AD, neuronal loss was most severe and best correlated with the duration of illness in the LC, rather than in NB as traditionally expected, suggesting that the former 2 nuclei may share common pathogenetic susceptibilities.
Abstract: Context Alzheimer disease (AD) and Parkinson disease (PD) are associated with neuronal degeneration in major subcortical nuclei, but few studies have examined the neuronal degeneration in these nuclei concurrently. Objective To identify clinical and pathological correlates of neuronal loss in the nucleus basalis (NB), locus coeruleus (LC), and substantia nigra pars compacta (SN) in AD and PD. Design The study sample comprised 86 cases with pathologically confirmed AD, 19 cases with PD, and 13 healthy elderly control subjects. The number of nucleolated neurons was counted in representative sections of the NB, LC, and SN. Effect sizes (ES) were computed to determine the standardized difference in cell counts relative to healthy controls. Results Cases of AD showed the greatest neuronal loss in the LC (ES = 3.16) followed by the NB (ES = 1.10), but variable loss in the SN (ES = 0.16). Cases of PD also showed the greatest neuronal loss in the LC (ES = 6.47), followed by the SN (ES = 2.58) and the NB (ES = 0.85). Significant correlations were found between the number of neurons in the NB and LC in PD ( r = 0.54, P r = 0.24, P Conclusions For both AD and PD the greatest neuronal loss was found in the LC. In AD, neuronal loss was most severe and best correlated with the duration of illness in the LC, rather than in NB as traditionally expected. Correlations between neuronal loss in the LC and NB (but not SN) in both PD and AD suggest that the former 2 nuclei may share common pathogenetic susceptibilities. Given the prominent loss of neurons in the LC, detection and treatment of noradrenergic deficiencies warrant attention in both AD and PD.
886 citations
TL;DR: This paper reviews recent studies that have investigated the mechanisms used by the nervous system to solve estimation and decision problems, which show that human behaviour is close to that predicted by Bayesian Decision Theory.
764 citations
TL;DR: In addition to degeneration of the nigrostriatal dopaminergic pathway, a variety of neuronal systems are involved, causing multiple neuromediator dysfunctions that account for the complex patterns of functional deficits.
Abstract: In Parkinson's disease (PD), in addition to degeneration of the nigrostriatal dopaminergic pathway, a variety of neuronal systems are involved, causing multiple neuromediator dysfunctions that account for the complex patterns of functional deficits. Degeneration affects the dopaminergic mesocorticolimbic system, the noradrenergic locus ceruleus (oral parts) and motor vagal nucleus, the serotonergic raphe nuclei, the cholinergic nucleus basalis of Meynert, pedunculopontine nucleus pars compacta, Westphal-Edinger nucleus, and many peptidergic brainstem nuclei. Cell losses in subcortical projection nuclei range from 30 to 90% of controls; they are more severe in depressed and demented PD patients. Most of the lesions are region-specific, affecting not all neurons containing a specific transmitter or harboring Lewy bodies. In contrast to Alzheimer's disease (AD), subcortical system lesions in Parkinson's disease appear not to be related to cortical pathology, suggesting independent or concomitant degeneration. The pathogenesis of multiple-system changes contributing to chemical pathology and clinical course of Parkinson's disease are unknown.
661 citations