Praveen Dayalu

Altered Resting State Cortico-Striatal Connectivity in Mild to Moderate Stage Parkinson's Disease

Parkinsons disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI in mild to moderate stage Parkinsons patients on and off l-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off l-DOPA compared to controls. This enhanced connectivity was down-regulated by l-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off l-DOPA exhibited increased power in the frequency band 0.02–0.05 Hz compared to controls and to PD on l-DOPA. The l-DOPA associated decrease in the power of this frequency range modulated the l-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the l-DOPA associated decrease in power in this frequency band correlated with the l-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and l-DOPA modulate striatal resting state BOLD signal oscillations and cortico-striatal network coherence.

Effect of Dopaminergic Medications on the Time Course of Explicit Motor Sequence Learning in Parkinson's Disease

The capacity to learn new motor sequences is fundamental to adaptive motor behavior. The early phase of motor sequence learning relies on the ventral and anterior striatal circuitry, whereas the late phase relies on the dorsal and posterior striatal circuitry. Early Parkinsons disease (PD) is mainly characterized by dopaminergic denervation of the dorsal and posterior striatum while sparing anterior and ventral regions. Dopaminergic medication improves dorsal and posterior striatum function by compensating for the loss of dopamine. However, previous work has shown that dopaminergic medication interferes with the ventral and anterior striatum function by overdosing this relatively intact structure in early-state PD. Here we test whether these effects are also observed over the time course of motor sequence learning. Fourteen PD patients ON and OFF dopaminergic medications and 11 healthy age-matched control participants performed an explicit motor sequence learning task. When sequence learning was compared across different learning phases in patients ON and OFF medication, a significant impairment associated with medication was observed in the early relative to later phases of learning. The rate of learning in the early phase measured trial by trial in patients ON medication was significantly slower than that in controls and when patients were OFF medication. No significant impairment was found in the later learning phases. These results demonstrate that dopaminergic medications may selectively impair early-phase motor sequence learning. These results extend and generalize the dopamine overdose effects previously reported for (antero)ventral striatum-mediated cognitive tasks to motor sequence learning.

Antipsychotic-induced extrapyramidal symptoms and their management

Background: Antipsychotic drugs have revolutionized the management of psychosis. Unfortunately, these drugs may cause a variety of distressing acute and delayed movement disorders, collectively known as ‘extrapyramidal symptoms’ (EPS). Objective: This review summarizes the current knowledge of the phenomenology, epidemiology, and pathophysiology of EPS, while highlighting their prevention and management. Methods: The review is limited to movement disorders resulting from typical and atypical antipsychotics. Recent and higher-quality evidence is emphasized. Conclusion: The pathophysiology of these disorders is still unclear. The use of atypical antipsychotics may have reduced EPS but has far from eliminated them. Available treatment options are often disappointing, especially for akathisia and the tardive syndromes. Future work will identify better treatments for these symptoms, as well as new antipsychotic agents that do not cause EPS.

Huntington disease: pathogenesis and treatment.

Huntington disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, culminating in death. It is caused by an expanded CAG repeat in the huntingtin gene. Even years before symptoms become overt, mutation carriers show subtle but progressive striatal and cerebral white matter atrophy by volumetric MRI. Although there is currently no direct treatment of HD, management options are available for several symptoms. A better understanding of HD pathogenesis, and more sophisticated clinical trials using newer biomarkers, may lead to meaningful treatments. This article reviews the current knowledge of HD pathogenesis and treatment.

l-DOPA changes ventral striatum recruitment during motor sequence learning in Parkinson's disease

We previously reported a differential effect of dopaminergic medication across the time course of motor sequence learning in early stage Parkinsons (PD) patients [1]. There was a medication-associated impairment specific to the early phase of learning. In the current study, we investigated the BOLD responses associated with this deleterious medication effect on motor sequence learning. We hypothesized that levodopa (l-DOPA) would negatively affect the recruitment of the ventral striatal circuitry during the early phase of learning. Seventeen early stage PD patients ON and OFF l-DOPA and 21 healthy control participants performed an explicit motor sequence learning task inside the MRI scanner. We observed sequence learning-specific activation during the early phase in the ventral putamen for controls and PD OFF but not for PD ON l-DOPA. A comparison of activation between PD OFF and PD ON showed that activation within the ventral putamen was decreased in PD ON compared to PD OFF. The extent of the l-DOPA associated activation decrease in the ventral putamen showed a small, positive correlation with the degree of sequence learning performance decrease in the early phase of learning (r=0.45-0.54 across measures, p<0.05, one-tailed). These findings provide evidence for the negative effects of l-DOPA in PD patients on the ventral putamen circuitry involved in early motor sequence learning, and provide support for a role of this structure in the sequence learning process.

Risk of sleep-disordered breathing in Parkinson's disease

ObjectiveThe objective of this study is to assess the risk of sleep-disordered breathing (SDB) in patients with Parkinsons disease (PD) in a cross-sectional survey of PD subjects and controls in a university-based movement disorders clinic.MethodsOne hundred thirty-four consecutive PD subjects and 94 control subjects without prior diagnosis of SDB were assessed. Participants were assessed with clinical history, Unified Parkinsons Disease Rating Scale, Geriatric Depression Scale, Berlin Questionnaire to classify SDB risk, Epworth Sleepiness Scale, Parkinsons Disease Sleep Scale, and SF-36 to examine quality of life. The presence of risk for SDB was assessed by the Berlin Questionnaire.ResultsHigh risk for SDB was apparent in 66 (49.3%) of the PD patients and 32 (34.8%) of the controls. After adjustment for age, gender, and body mass index (BMI), PD subjects in comparison to controls showed higher risk for SBD (odds ratio = 2.81; 95% confidence interval, 1.36–5.82). Quality of life (physical component score) was significantly diminished in PD patients at high risk for SDB. PD severity did not correlate well with SDB risk. PD patients at high risk for SDB had higher BMIs and Epworth scores.ConclusionsPD patients have features suggesting increased risk for SDB. This frequently undiagnosed sleep disorder may have a substantial impact on quality of life of PD patients.

Altered cerebellar connectivity in Parkinson's patients ON and OFF L-DOPA medication.

Although nigrostriatal changes are most commonly affiliated with Parkinsons disease, the role of the cerebellum in Parkinsons has become increasingly apparent. The present study used lobule-based cerebellar resting state functional connectivity to (1) compare cerebellar-whole brain and cerebellar-cerebellar connectivity in Parkinsons patients both ON and OFF L-DOPA medication and controls, and to (2) relate variations in cerebellar connectivity to behavioral performance. Results indicated that, when contrasted to the control group, Parkinsons patients OFF medication had increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity, whereas Parkinsons patients ON medication had decreased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity. Moreover, analyses relating levels of cerebellar connectivity to behavioral measures demonstrated that, within each group, increased levels of connectivity were most often associated with improved cognitive and motor performance, but there were several instances where increased connectivity was related to poorer performance. Overall, the present study found medication-variant cerebellar connectivity in Parkinsons patients, further demonstrating cerebellar changes associated with Parkinsons disease and the moderating effects of medication.

Stiff person syndrome and other anti-GAD-associated neurologic disorders

Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients.

HDQLIFE: the development of two new computer adaptive tests for use in Huntington disease, Speech Difficulties, and Swallowing Difficulties

PurposeHuntington disease (HD) is an autosomal dominant neurodegenerative disease which results in several progressive symptoms, including bulbar dysfunction (i.e., speech and swallowing difficulties). Although difficulties in speech and swallowing in HD have a negative impact on health-related quality of life, no patient-reported outcome measure exists to capture these difficulties that are specific to HD. Thus, we developed a new patient-reported outcome measure for use in the Huntington Disease Health-Related Quality of Life (HDQLIFE) Measurement System that focused on the impact that difficulties with speech and swallowing have on HRQOL in HD.MethodsFive hundred and seven individuals with prodromal and/or manifest HD completed 47 newly developed items examining speech and swallowing difficulties. Unidimensional item pools were identified using exploratory factor analysis and confirmatory factor analysis (EFA and CFA, respectively). Item response theory (IRT) was used to calibrate the final measures.ResultsEFA and CFA identified two separate unidimensional sets of items: Speech Difficulties (27 items) and Swallowing Difficulties (16 items). Items were calibrated separately for these two measures and resulted in item banks that can be administered as computer adaptive tests (CATs) and/or 6-item, static short forms. Reliability of both of these measures was supported through high correlations between the simulated CAT scores and the full item bank.ConclusionsCATs and 6-item calibrated short forms were developed for HDQLIFE Speech Difficulties and HDQLIFE Swallowing Difficulties. These measures both demonstrate excellent psychometric properties and may have clinical utility in other populations where speech and swallowing difficulties are prevalent.

The Pattern of Striatal Dopaminergic Denervation Explains Sensorimotor Synchronization Accuracy in Parkinson’s Disease

The basal ganglia are thought to play a critical role in duration perception and production. However, experimental evidence for impaired temporal processing in Parkinsons disease (PD) patients is mixed. This study examined the association between striatal dopaminergic denervation in PD patients and sensorimotor synchronization. Twenty-eight mild-to-moderate stage PD patients synchronized finger taps to tone sequences of either 500 ms, 1000 ms or 1500 ms time intervals while ON levodopa (l-DOPA) or placebo pill (on separate test days) with the index finger of their more and less affected hands. We measured the accuracy and variability of synchronization. In a separate session, patients underwent (11)C-dihydrotetrabenazine ((11)C-DTBZ) PET scanning to measure in vivo striatal dopaminergic denervation. Patients were less accurate synchronizing to the 500 ms target time interval, compared to the 1000 ms and 1500 ms time intervals, but neither medication state nor hand affected accuracy; medication state, hand nor the target time interval affected synchronization variability. Regression analyses revealed no strong relationships between synchronization accuracy or variability and striatal dopaminergic denervation. We performed a cluster analysis on the degree of dopaminergic denervation to determine whether patient subgroup differences underlie our results. Three patient subgroups showed behavioral differences in synchronization accuracy, but not variability, paralleling their pattern of denervation. These findings provide further evidence for the role of the basal ganglia and dopamine in duration production and suggest that the degree of striatal dopaminergic denervation may explain the heterogeneity of performance between PD patients on the sensorimotor synchronization task.