Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine

The primate prefrontal cortex (PFC) subserves our highest order cognitive operations, and yet is tremendously dependent on a precise neurochemical environment for proper functioning. Depletion of noradrenaline and dopamine, or of acetylcholine from the dorsolateral PFC (dlPFC), is as devastating as removing the cortex itself, and serotonergic influences are also critical to proper functioning of the orbital and medial PFC. Most neuromodulators have a narrow inverted U dose response, which coordinates arousal state with cognitive state, and contributes to cognitive deficits with fatigue or uncontrollable stress. Studies in monkeys have revealed the molecular signaling mechanisms that govern the generation and modulation of mental representations by the dlPFC, allowing dynamic regulation of network strength, a process that requires tight regulation to prevent toxic actions, e.g., as occurs with advanced age. Brain imaging studies in humans have observed drug and genotype influences on a range of cognitive tasks and on PFC circuit functional connectivity, e.g., showing that catecholamines stabilize representations in a baseline-dependent manner. Research in monkeys has already led to new treatments for cognitive disorders in humans, encouraging future research in this important field

Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications

The neuropsychological basis of attentional set-shifting, task-set switching and stop-signal inhibition is reviewed through comparative studies of humans and experimental animals. Using human functional neuroimaging, plus neuropsychological investigation of patients with frontal damage quantified by structural magnetic resonance imaging, and through parallels with effects of specific lesions of the prefrontal cortex (PFC) and striatum in rats and marmosets, it is possible to define both distinct and overlapping loci for tasks such as extra-dimensional shifting and reversal learning, stop-signal reaction time and task-set switching. Notably, most of the paradigms implicate a locus in the right PFC, specifically the right inferior frontal gyrus, possibly associated with processes of response inhibition. The neurochemical modulation of fronto-striatal circuitry in parallel with effects on task performance has been investigated using specific neuropharmacological agents in animals and by human psychopharmacological investigations, sometimes in conjunction with functional imaging. Evidence is provided for double dissociations of effects of manipulations of prefrontal cortical catecholamine and indoleamine (5-HT) systems that have considerable implications in the treatment of disorders such as Parkinson's disease, attention deficit/hyperactivity disorder and depression, as well as in theoretical notions of how ‘fronto-executive’ functions are subject to state-dependent influences, probably related to stress, arousal and motivation