No one doubts that the cause of Parkinson’s Disease is the death of the dopamine neurons in the substantia nigra-pars compacta. Indeed, all the major treatments were designed to replace the missing neurotransmitter; until deep brain stimulation (DBS) came along. That breakthrough used the hypothesized basal ganglia circuit to interfere in a constructive way with the consequences of the dopamine loss. While we explored the effects of stimulation in the subthalamic nucleus in animal models of the disease symptoms, it was obvious that as well as interfering in the basal ganglia, DBS also had dramatic actions in the cortex, (Li et al., 2007). Each stimulus had a considerable chance of exciting cortical layer V cells antidromically along the axon that passed just under the electrode in isofluorine aneasthetised rats. Of course, this was in a small rodent – but the same phenomenon had already been described in patients. Single pulses at the subthalamic electrode induced a short latency (~3ms) positive going wave in the EEG: the signature of antidromic activation of deep cortical neurons. In freely moving rats we first showed that recovery from akinesia depended on an antidromic response (Dejean et al., 2009) in cortex, and then with other collaborators we were able to show that the stochastic activation of these layer 5 cells was able to disrupt the correlation of cortical neuron firing with the beta wave in the EEG (Li et al., 2012). Such disruption is a signature of curative actions on the disease symptoms. Finally, the final output from the basal ganglia arrives back at the cerebral cortex (Arbuthnott et al., 1990), is this where the symptoms originate? If it is, can we develop methods to fix the symptoms? References Arbuthnott, G., Macleod, N., Maxwell, D. & Wright, A. (1990) Distribution and synaptic contacts of the cortical terminals arising from neurons in the rat ventromedial thalamic nucleus. Neuroscience, 38, 47-60. Dejean, C., Hyland, B. & Arbuthnott, G. (2009) Cortical Effects of Subthalamic Stimulation Correlate with Behavioral Recovery from Dopamine Antagonist Induced Akinesia. Cereb. Cortex, 19, 1055-1063. Li, Q., Ke, Y., Chan, D.C., Qian, Z.M., Yung, K.K., Ko, H., Arbuthnott, G.W. & Yung, W.H. (2012) Therapeutic deep brain stimulation in Parkinsonian rats directly influences motor cortex. Neuron, 76, 1030-1041. Li, S., Arbuthnott, G.W., Jutras, M.J., Goldberg, J.A. & Jaeger, D. (2007) Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation. J Neurophysiol, 98, 3525-3537. <!–![endif]—->