The aim of our study was to investigate the relation between substantia nigra (SN) echomorphology and indices of motor cortex excitability. Nigral hyperechogenicity in healthy individuals is thought to represent an SN abnormality or predisposition to Parkinson's disease (PD) and its prevalence is greater in the very old. Our study involved 20 old healthy subjects (aged 72-84 years) known to have normal (n=10) or abnormal (n=10) SN echomorphology. All were in good health with no overt neurological signs. SN morphology was assessed with transcranial sonography through the pre-auricular bone window. Motor cortical excitability and intracortical inhibition were assessed with transcranial magnetic stimulation (TMS) over the first dorsal interosseus motor area. Single stimuli were delivered during relaxation and voluntary contraction and paired stimuli were delivered during relaxation. Each cortical hemisphere was analysed separately. The response to single-pulse TMS (in motor cortex ipsilateral to the target SN) did not differ between groups. However, a significant difference between groups was observed in the paired pulse paradigm (conditioning stimulus intensity: 70% resting motor threshold; interstimulus interval: 2 ms). The conditioned motor evoked potential amplitude was significantly larger ipsilateral to the hyperechogenic SN than in controls (P=0.014). Thus, healthy subjects with SN hyperechogenicity exhibit significantly less intracortical inhibition within the motor cortex than subjects with normal echomorphology. Decreased intracortical inhibition is also observed in PD patients. This study provides further evidence that SN hyperechogenicity in healthy individuals is associated with changes characteristic of PD supporting a role for this feature as a vulnerability marker or state marker for subtle nigral dopaminergic dysfunction. ; G. Todd, J.L. Taylor, D. Baumann, J.E. Butler, S.R. Duma, M. Hayes, F. Carew-Jones, O. Piguet, S. Behnke, M.C. Ridding, D. Berg and K.L. Double