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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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Time perception paradigm and task performance.A) Trial events for the auditory and visual conditions of the time perception task. Trials were preceded by a 500 ms warning signal (i.e., flashing yellow fixation cross and a mixed 700 Hz auditory tone). At trial onset, an auditory or visual standard-interval (SI) (1200 or 1800 ms) was presented and followed by a delay (6800 or 6200 ms). At 8 s post-trial onset, a comparison interval (CI) of the same modality was presented. Image acquisition (TR  =  2 s) was pegged to the onsets on the SI and CI. The first 12 s of a trial (i.e., equivalent to 6 TRs) constituted the encoding phase. The last 12 s of a trial constituted the decision phase. B) Mean (standard error bars) accuracy for the auditory (left) and visual (right) conditions in the control group and PD OFF and ON conditions. Accuracy data were converted to the mean percent longer, and averaged across the two SI conditions and their respective CIs. On the x axis, ±7, 14, and 21 designate CIs that were 7%, 14%, and 21% shorter (negative values) or longer (positive values) than the SI.
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pone-0017461-g001: Time perception paradigm and task performance.A) Trial events for the auditory and visual conditions of the time perception task. Trials were preceded by a 500 ms warning signal (i.e., flashing yellow fixation cross and a mixed 700 Hz auditory tone). At trial onset, an auditory or visual standard-interval (SI) (1200 or 1800 ms) was presented and followed by a delay (6800 or 6200 ms). At 8 s post-trial onset, a comparison interval (CI) of the same modality was presented. Image acquisition (TR  =  2 s) was pegged to the onsets on the SI and CI. The first 12 s of a trial (i.e., equivalent to 6 TRs) constituted the encoding phase. The last 12 s of a trial constituted the decision phase. B) Mean (standard error bars) accuracy for the auditory (left) and visual (right) conditions in the control group and PD OFF and ON conditions. Accuracy data were converted to the mean percent longer, and averaged across the two SI conditions and their respective CIs. On the x axis, ±7, 14, and 21 designate CIs that were 7%, 14%, and 21% shorter (negative values) or longer (positive values) than the SI.

Mentions: In the time perception task (Figure 1A), subjects attended to the duration of successively presented pairs of filled-auditory or visual stimuli, and then judged whether the second stimulus was shorter or longer than the first. Throughout the experiment, the subject maintained fixation on a white cross at the center of the display. One second before trial onset, a warning signal (i.e., flashing yellow cross and mixed 700-Hz tone) appeared for 500 ms followed by a 500 ms delay. Trial onset began with presentation of an auditory (1000 Hz pure tone) or visual (blue circle) SI that lasted 1200 or 1800 ms, and was respectively followed by a 6800 or 6200 ms delay. Then a CI of the same modality was presented, after which the subject indicated if it was shorter or longer than the SI by pressing a key with the right index or middle finger. For each SI, there were 3 shorter and 3 longer CIs that differed from the SI by successive increments of ±7%. Two SIs were used to help ensure that subjects encoded signal duration on each trial. The analyses collapsed across SI duration. The analyses also collapsed across signal modality, as there were no group differences in timing auditory and visual signals (see Results section), consistent with other reports [7]. Accuracy and reaction time (RT; from offset of the CI to key press) were measured. We did not include a sensorimotor control task since processing in sensory areas was of interest to our study.


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)

Time perception paradigm and task performance.A) Trial events for the auditory and visual conditions of the time perception task. Trials were preceded by a 500 ms warning signal (i.e., flashing yellow fixation cross and a mixed 700 Hz auditory tone). At trial onset, an auditory or visual standard-interval (SI) (1200 or 1800 ms) was presented and followed by a delay (6800 or 6200 ms). At 8 s post-trial onset, a comparison interval (CI) of the same modality was presented. Image acquisition (TR  =  2 s) was pegged to the onsets on the SI and CI. The first 12 s of a trial (i.e., equivalent to 6 TRs) constituted the encoding phase. The last 12 s of a trial constituted the decision phase. B) Mean (standard error bars) accuracy for the auditory (left) and visual (right) conditions in the control group and PD OFF and ON conditions. Accuracy data were converted to the mean percent longer, and averaged across the two SI conditions and their respective CIs. On the x axis, ±7, 14, and 21 designate CIs that were 7%, 14%, and 21% shorter (negative values) or longer (positive values) than the SI.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3045463&req=5

pone-0017461-g001: Time perception paradigm and task performance.A) Trial events for the auditory and visual conditions of the time perception task. Trials were preceded by a 500 ms warning signal (i.e., flashing yellow fixation cross and a mixed 700 Hz auditory tone). At trial onset, an auditory or visual standard-interval (SI) (1200 or 1800 ms) was presented and followed by a delay (6800 or 6200 ms). At 8 s post-trial onset, a comparison interval (CI) of the same modality was presented. Image acquisition (TR  =  2 s) was pegged to the onsets on the SI and CI. The first 12 s of a trial (i.e., equivalent to 6 TRs) constituted the encoding phase. The last 12 s of a trial constituted the decision phase. B) Mean (standard error bars) accuracy for the auditory (left) and visual (right) conditions in the control group and PD OFF and ON conditions. Accuracy data were converted to the mean percent longer, and averaged across the two SI conditions and their respective CIs. On the x axis, ±7, 14, and 21 designate CIs that were 7%, 14%, and 21% shorter (negative values) or longer (positive values) than the SI.
Mentions: In the time perception task (Figure 1A), subjects attended to the duration of successively presented pairs of filled-auditory or visual stimuli, and then judged whether the second stimulus was shorter or longer than the first. Throughout the experiment, the subject maintained fixation on a white cross at the center of the display. One second before trial onset, a warning signal (i.e., flashing yellow cross and mixed 700-Hz tone) appeared for 500 ms followed by a 500 ms delay. Trial onset began with presentation of an auditory (1000 Hz pure tone) or visual (blue circle) SI that lasted 1200 or 1800 ms, and was respectively followed by a 6800 or 6200 ms delay. Then a CI of the same modality was presented, after which the subject indicated if it was shorter or longer than the SI by pressing a key with the right index or middle finger. For each SI, there were 3 shorter and 3 longer CIs that differed from the SI by successive increments of ±7%. Two SIs were used to help ensure that subjects encoded signal duration on each trial. The analyses collapsed across SI duration. The analyses also collapsed across signal modality, as there were no group differences in timing auditory and visual signals (see Results section), consistent with other reports [7]. Accuracy and reaction time (RT; from offset of the CI to key press) were measured. We did not include a sensorimotor control task since processing in sensory areas was of interest to our study.

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