Motor loop dysfunction causes impaired cognitive sequencing in patients suffering from Parkinson's disease

Cognitive impairment in Parkinson's disease (PD) is often attributed to dopamine deficiency in the prefrontal-basal ganglia-thalamo-cortical loops. Although recent studies point to a close interplay between motor and cognitive abilities in PD, the so-called "motor loop" connecting supplementary motor area (SMA) and putamen has been considered solely with regard to the patients' motor impairment. Our study challenges this view by testing patients with the serial prediction task (SPT), a cognitive task that requires participants to predict stimulus sequences and particularly engages premotor sites of the motor loop. We hypothesised that affection of the motor loop causes impaired SPT performance, especially when the internal sequence representation is challenged by suspension of external stimuli. As shown for motor tasks, we further expected this impairment to be compensated by hyperactivity of the lateral premotor cortex (PM). We tested 16 male PD patients ON and OFF dopaminergic medication and 16 male age-matched healthy controls in an functional Magnetic Resonance Imaging study. All subjects performed two versions of the SPT: one with on-going sequences (SPT0), and one with sequences containing non-informative wildcards (SPT+) increasing the demands on mnemonic sequence representation. Patients ON (compared to controls) revealed an impaired performance coming along with hypoactivity of SMA and putamen. Patients OFF compared to ON medication, while showing poorer performance, exhibited a significantly increased PM activity for SPT+ vs. SPT0. Furthermore, patients' performance positively co-varied with PM activity, corroborating a compensatory account. Our data reveal a contribution of the motor loop to cognitive impairment in PD, and suggest a close interplay of SMA and PM beyond motor control.