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Neurobehavioral mechanisms of temporal processing deficits in Parkinson's disease.

Harrington DL, Castillo GN, Greenberg PA, Song DD, Lessig S, Lee RR, Rao SM - PLoS ONE (2011)

Bottom Line: First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction.Finally, DA therapy did not alleviate timing deficits.However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

View Article: PubMed Central - PubMed

Affiliation: Research, Neurology, and Radiology Services, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America. dharrington@ucsd.edu

ABSTRACT

Background: Parkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.

Methodology/findings: The present study addressed these issues by testing controls and PD volunteers 'on' and 'off' DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.

Conclusions/significance: Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

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Scatter plots showing significant striatal-cortical connectivity that was modulated by medication.Scatter plots show the relationship between striatal and cortical activity as a function of medication state in representative regions. Linear regression fits are overlaid on the scatter plots. Gray squares and lines  =  PD OFF condition; black triangles and lines  =  PD On condition. Bracketed numbers refer to regions listed in Table 4.
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pone-0017461-g007: Scatter plots showing significant striatal-cortical connectivity that was modulated by medication.Scatter plots show the relationship between striatal and cortical activity as a function of medication state in representative regions. Linear regression fits are overlaid on the scatter plots. Gray squares and lines  =  PD OFF condition; black triangles and lines  =  PD On condition. Bracketed numbers refer to regions listed in Table 4.

Mentions: Effective connectivity analyses showed that interactions of the striatum with the cortex were modulated by DA therapy, but only in the decision phase. Table 4 and Figure 6 show that DA therapy significantly modulated interactions between the striatum and the cortex (i.e., SMA, precentral and postcentral gyrus, superior frontal gyrus (SFG), MFG, superior and inferior parietal cortex, precuneus, and insula), but not the cerebellum. Figure 7 graphs representative PPI. Corticostriatal interactions were stronger OFF than ON medication. An exception was stronger connectivity ON than OFF therapy between the left putamen and the left SFG (BA 6).


Neurobehavioral mechanisms of temporal processing deficits in Parkinson's disease.

Harrington DL, Castillo GN, Greenberg PA, Song DD, Lessig S, Lee RR, Rao SM - PLoS ONE (2011)

Scatter plots showing significant striatal-cortical connectivity that was modulated by medication.Scatter plots show the relationship between striatal and cortical activity as a function of medication state in representative regions. Linear regression fits are overlaid on the scatter plots. Gray squares and lines  =  PD OFF condition; black triangles and lines  =  PD On condition. Bracketed numbers refer to regions listed in Table 4.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045463&req=5

pone-0017461-g007: Scatter plots showing significant striatal-cortical connectivity that was modulated by medication.Scatter plots show the relationship between striatal and cortical activity as a function of medication state in representative regions. Linear regression fits are overlaid on the scatter plots. Gray squares and lines  =  PD OFF condition; black triangles and lines  =  PD On condition. Bracketed numbers refer to regions listed in Table 4.
Mentions: Effective connectivity analyses showed that interactions of the striatum with the cortex were modulated by DA therapy, but only in the decision phase. Table 4 and Figure 6 show that DA therapy significantly modulated interactions between the striatum and the cortex (i.e., SMA, precentral and postcentral gyrus, superior frontal gyrus (SFG), MFG, superior and inferior parietal cortex, precuneus, and insula), but not the cerebellum. Figure 7 graphs representative PPI. Corticostriatal interactions were stronger OFF than ON medication. An exception was stronger connectivity ON than OFF therapy between the left putamen and the left SFG (BA 6).

Bottom Line: First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction.Finally, DA therapy did not alleviate timing deficits.However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

View Article: PubMed Central - PubMed

Affiliation: Research, Neurology, and Radiology Services, Veterans Affairs San Diego Healthcare System, San Diego, California, United States of America. dharrington@ucsd.edu

ABSTRACT

Background: Parkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.

Methodology/findings: The present study addressed these issues by testing controls and PD volunteers 'on' and 'off' DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.

Conclusions/significance: Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.

Show MeSH
Related in: MedlinePlus