Corrie R. Camalier

The mismatch negativity (MMN) is an event-related potential component seen in response to unexpected “novel” stimuli, such as in an auditory oddball task. The MMN is of wide interest and application, but the neural responses that generate it are poorly understood. This is in part due to differences in design and focus between animal and human oddball paradigms. For example, one of the main explanatory models, the “predictive error hypothesis”, posits differences in timing and selectivity between signals carried in auditory and prefrontal cortex. However these predictions have not been fully tested because 1) noninvasive techniques used in humans lack the combined spatial and temporal precision necessary for these comparisons, and 2) single-neuron studies in animal models, which combine spatial and temporal precision, have not focused on higher order contributions to novelty signals. In addition, accounts of the MMN traditionally do not address contributions from subcortical areas known to be involved in novelty detection, such as the amygdala. To better constrain hypotheses and to address methodological gaps between human and animal studies, we recorded single neuron activity from the auditory cortex, dorsolateral prefrontal cortex, and basolateral amygdala of two macaque monkeys during an auditory oddball paradigm modeled after that used in humans. Consistent with predictions of the predictive error hypothesis, novelty signals in prefrontal cortex were generally later than in auditory cortex, and were abstracted from stimulus-specific effects seen in auditory cortex. However, we found signals in amygdala that were comparable in magnitude and timing to those in prefrontal cortex, and both prefrontal and amygdala signals were generally much weaker than those in auditory cortex. These observations place useful quantitative constraints on putative generators of the auditory oddball-based MMN, and additionally indicate that there are subcortical areas, such as the amygdala, that may be involved in novelty detection in an auditory oddball paradigm.

Patients with Parkinson’s disease experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn-Yahr III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery (DBS), the ability to identify this nucleus in early stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN nucleus in fifteen patients with early Parkinson’s disease (Hoehn-Yahr II), using a combination of image guided surgery, microelectrode recordings and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates, root mean squared activity) have previously been found to be lower than in later stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson’s patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early stage Parkinson’s disease using traditional methods.