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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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Related in: MedlinePlus

Functional ROI for the encoding (A) and decision phases (B).Functional ROIs were derived from conjoining activation maps in Figures S1 and S2, respectively. Yellow regions designate significant group (Control vs. PD OFF) differences in activation; red regions indicate no significant group differences. Brain activation is projected onto the lateral and medial surfaces of the left and right hemispheres (rows 1 and 2), the anterior and posterior surfaces of the cerebellum (row 3), and the left and right basal ganglia (row 4). See Table S3 for details about individual fROI.
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pone-0017461-g003: Functional ROI for the encoding (A) and decision phases (B).Functional ROIs were derived from conjoining activation maps in Figures S1 and S2, respectively. Yellow regions designate significant group (Control vs. PD OFF) differences in activation; red regions indicate no significant group differences. Brain activation is projected onto the lateral and medial surfaces of the left and right hemispheres (rows 1 and 2), the anterior and posterior surfaces of the cerebellum (row 3), and the left and right basal ganglia (row 4). See Table S3 for details about individual fROI.

Mentions: The conjoined fMRI activation-masks in Figure 3 show that similar regions of activation were found during both phases of the trial (see Table S3 for details about activation foci). Figure 3 also shows that group differences were found in only a subset of these regions (i.e., yellow), and were partially related to the behavioral context. For example, the PD OFF group exhibited abnormal preSMA/SMA/cingulate, precentral, middle-frontal, parietal, insula, inferior-temporal, right-parahippocampus, and lateral-cerebellum activation during the encoding phase. In contrast, posterior-cingulate and left-parahippocampus activations were abnormal during the decision phase. Only the striatum and vermis exhibited abnormal activation during both phases. We now turn to the statistical analyses in support of these observations.


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)

Functional ROI for the encoding (A) and decision phases (B).Functional ROIs were derived from conjoining activation maps in Figures S1 and S2, respectively. Yellow regions designate significant group (Control vs. PD OFF) differences in activation; red regions indicate no significant group differences. Brain activation is projected onto the lateral and medial surfaces of the left and right hemispheres (rows 1 and 2), the anterior and posterior surfaces of the cerebellum (row 3), and the left and right basal ganglia (row 4). See Table S3 for details about individual fROI.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017461-g003: Functional ROI for the encoding (A) and decision phases (B).Functional ROIs were derived from conjoining activation maps in Figures S1 and S2, respectively. Yellow regions designate significant group (Control vs. PD OFF) differences in activation; red regions indicate no significant group differences. Brain activation is projected onto the lateral and medial surfaces of the left and right hemispheres (rows 1 and 2), the anterior and posterior surfaces of the cerebellum (row 3), and the left and right basal ganglia (row 4). See Table S3 for details about individual fROI.
Mentions: The conjoined fMRI activation-masks in Figure 3 show that similar regions of activation were found during both phases of the trial (see Table S3 for details about activation foci). Figure 3 also shows that group differences were found in only a subset of these regions (i.e., yellow), and were partially related to the behavioral context. For example, the PD OFF group exhibited abnormal preSMA/SMA/cingulate, precentral, middle-frontal, parietal, insula, inferior-temporal, right-parahippocampus, and lateral-cerebellum activation during the encoding phase. In contrast, posterior-cingulate and left-parahippocampus activations were abnormal during the decision phase. Only the striatum and vermis exhibited abnormal activation during both phases. We now turn to the statistical analyses in support of these observations.

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