Dopaminergic modulation of striato-frontal connectivity during motor timing in Parkinson's disease

Abstract

Patients with Parkinson's disease experience motor and perceptual timing difficulties, which are ameliorated by dopaminergic medication. We investigated the neural correlates of motor timing in Parkinson's disease, including the effects of dopaminergic medication on patterns of brain activation. Eight patients with Parkinson's disease and eight healthy controls were scanned with H(15)(2)O positron emission tomography while engaged in three tasks: synchronization (right index finger tapping in synchrony with a tone presented at 1 Hz), continuation (tapping at 1 Hz in the absence of a tone), and a control simple reaction time task. During the first 6 scans, the patients were assessed after overnight withdrawal of medication. Scans 7-12 were completed with the patients in the 'ON' state, after injections of apomorphine, a dopamine receptor agonist. For the healthy controls, relative to the control reaction time task, motor timing (synchronization + continuation) was associated with significantly greater activation in left medial prefrontal cortex (Brodmann area 10, 32), right hippocampus, bilateral angular gyrus (Brodmann area 39), left posterior cingulate (Brodmann area 31) and left nucleus accumbens/caudate. This pattern of brain activation during motor timing was not observed for patients, who showed significantly greater activation in bilateral cerebellum, right thalamus and left midbrain/substantia nigra compared to the control participants. Relative to the externally-paced synchronization task, the internally controlled continuation task was associated with greater activation in the dorsolateral prefrontal cortex (Brodmann area 46/9) in both the control and Parkinson's disease groups. Analysis of medication-related effects indicated that cortical activation was significantly more predominant during motor timing when the patients were 'ON' medication, whereas pallidal and cerebellar activations were evident 'OFF' medication. Effective connectivity analysis established that activity in the left caudate nucleus was associated with increased activity in the right lentiform nucleus and cerebellum 'OFF' medication, and with increased activity in the prefrontal cortex 'ON' medication. These results suggest that in Parkinson's disease, in the 'OFF' medication state, excessive inhibitory pallidal outflow is associated with a lack of adequate frontal activation and reliance on the cerebellum for motor timing. In contrast, our results establish for the first time that administration of dopaminergic medication increases striatal-frontal connectivity between the caudate nucleus and prefrontal cortex during motor timing.

Prefrontal D1 dopamine signaling is required for temporal control

“…This process depends on the integrated activity of corticostriatal systems (1)(2)(3) and requires intact dopaminergic signaling (4). Patients with Parkinson disease with depleted dopamine have dramatically impaired temporal control (5).…”

Medial frontal ∼4-Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion

“…In the range of seconds, interval timing requires executive resources, such as working memory and attention to time (Brown 2006;Parker et al 2013), and is consistently impaired in patients with PD (Buhusi and Meck 2005;Malapani et al 1998;Merchant et al 2008). Because this task is highly conserved across mammalian species (Buhusi and Meck 2005;Merchant et al 2013), it can be rapidly trained in rodent models, facilitating mechanistic hypothesis testing (Drew et al 2003;Narayanan et al 2012).Controlling the timing of action requires the integrated activity of corticostriatal circuits (Hinton and Meck 2004;Matell and Meck 2004) that are dysfunctional in PD patients (Jahanshahi et al 2010). Recent work has demonstrated that the medial frontal cortex (MFC) is necessary for the temporal control of action.…”

D1-Dependent 4 Hz Oscillations and Ramping Activity in Rodent Medial Frontal Cortex during Interval Timing

“…Interval timing requires corticostriatal systems (Matell et al, 2003;Jahanshahi et al, 2010) including medial frontal cortex (MFC) and dorsal striatum (Coull et al, 2011). Inactivation of MFC in rodents profoundly impairs interval timing (Kim et al, 2009;.…”