The Organization of Prefrontal-Subthalamic Inputs in Primates Provides an Anatomical Substrate for Both Functional Specificity and Integration: Implications for Basal Ganglia Models and Deep Brain Stimulation

Abstract

The identification of a hyperdirect cortico-subthalamic nucleus connection highlighted the important role of the subthalamic nucleus (STN) in regulating behavior. However, this pathway was shown primarily from motor areas. Hyperdirect pathways associated with cognitive and motivational cortical regions are particularly relevant given recent data from deep brain stimulation, both for neurological and psychiatric disorders. Our experiments were designed to: demonstrate the existence and organization of prefrontal-STN projections, help delineate the ‘limbic’ STN, and determine whether convergence between cortico-STN fibers from functionally diverse cortical areas exists in the STN. We injected anterograde tracers in the ventromedial prefrontal, orbitofrontal, anterior cingulate and dorsal prefrontal cortices of Macaca nemestrina & M. fascicularis to analyze the organization of terminals and passing fibers in the STN. Results show a topographically organized prefrontal hyperdirect pathway in primates. Limbic areas project to the medial tip of the nucleus, straddling its border and extending into the lateral hypothalamus. Associative areas project to the medial half, motor areas to the lateral half. Limbic projections terminated primarily rostrally and motor projections more caudally. The extension of limbic projections into the lateral hypothalamus, suggests that this region be included in the STN. A high degree of convergence exists between projections from functionally diverse cortical areas, creating potentially important interfaces between terminal fields. Taken together, the results provide an anatomical substrate to extend the role of the hyperdirect pathway in models of basal ganglia function, and new keys for understanding deep brain stimulation effects on cognitive and motivational aspects of behavior.

Response inhibition rapidly increases single-neuron responses in the subthalamic nucleus of patients with Parkinson's disease

“…Therefore, we speculate that the absence of error-monitoring cells in PD might be related to a lower sampling of the STN subregions where these cells might be clustered. This idea would support a tripartite model of STN functional subterritories, in coherence with previous neuroimaging (Haynes & Haber, 2013;Karachi et al, 2005;Parent, 1990) and stimulation studies Lambert et al, 2011;Mallet et al, 2007;Sudhyadhom et al, 2007).…”

“…The dynamics of this network has been conceptualized in several computational models of response inhibition (Frank, 2006;Ratcliff & Frank, 2012;Wiecki & Frank, 2013) in which rapid suppression of a prepared move involves a fast stopping signal neurally implemented via a putative hyperdirect pathway (Monakow, Akert, & Kü nzle, 1978;Nambu, Takada, Inase, & Tokuno, 1996). This hyperdirect pathway assumes projections of the frontal cortex (pre-SMA, inferior frontal gyrus and anterior cingular cortices) onto the subthalamic nucleus (Haynes & Haber, 2013). This hypothesis is attractive, but it is currently only supported by a few intracerebral electrophysiological recordings in humans-during the stop signal task (SST)-showing that beta (15e35 Hz) oscillations of local field potentials (LFP) increased during stopping in the inferior frontal gyrus (Jha et al, 2015;Swann et al, 2009;Wessel, Conner, Aron, & Tandon, 2013) and in the STN at latencies that precede the time needed to cancel movements (stop signal reaction time, SSRT).…”

Subthalamic nucleus activity dissociates proactive and reactive inhibition in patients with Parkinson's disease

“…Anterograde tracers into STN pre-motor, limbic and associative areas have demonstrated the existence of a hyperdirect projection from these areas (Haynes and Haber, 2013), in addition to the hyperdirect motor loop (Monakow et al, 1978;Nambu et al, 1996). This suggests a major role of the hyperdirect premotor cortex-subthalamic entry to the basal ganglia relaying control on basal ganglia outflow in cognitive, limbic and motor activities.…”

Deep brain stimulation: a mechanistic and clinical update

“…Haynes and Haber recently illustrated the existence of a set of such prefrontal-STN hyperdirect connections in macaque monkeys. 77 Interestingly, projections from functionally diverse regions of cortex were found to converge on overlapping regions of the STN. This work, along with others, 5,106 also further helps to delineate the "associative-limbic" STN as the ventromedial STN, and includes the adjacent lateral hippocampus in the definition of the "limbic" STN.…”