Prefrontal cortex regulates inhibition and excitation in distributed neural networks

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Abstract

Prefrontal cortex provides both inhibitory and excitatory input to distributed neural circuits required to support performance in diverse tasks. Neurological patients with prefrontal damage are impaired in their ability to inhibit task-irrelevant information during behavioral tasks requiring performance over a delay. The observed enhancements of primary auditory and somatosensory cortical responses to task-irrelevant distractors suggest that prefrontal damage disrupts inhibitory modulation of inputs to primary sensory cortex, perhaps through abnormalities in a prefrontal-thalamic sensory gating system. Failure to suppress irrelevant sensory information results in increased neural noise, contributing to the deficits in decision making routinely observed in these patients. In addition to a critical role in inhibitory control of sensory flow to primary cortical regions, and tertiary prefrontal cortex also exerts excitatory input to activity in multiple sub-regions of secondary association cortex. Unilateral prefrontal damage results in multi-modal decreases in neural activity in posterior association cortex in the hemisphere ipsilateral to damage. This excitatory modulation is necessary to sustain neural activity during working memory. Thus, prefrontal cortex is able to sculpt behavior through parallel inhibitory and excitatory regulation of neural activity in distributed neural networks.

Introduction

In 1935 Jacobsen reported that monkeys with bilateral frontal lesions involving the sulcus principalis, a putative analogue of human dorsolateral prefrontal cortex (Brodmann areas 9 and 46: Rajkowska and Goldman-Rakic, 1995a, Rajkowska and Goldman-Rakic, 1995b; see Fig. 1), were severely impaired at delayed response tasks (Jacobsen, 1935). In delayed response tasks, subjects are initially presented with information necessary to perform a specific task. The experimenter then interposes a delay period before the animal or human is allowed to perform the task. Thus, for successful performance, the information must be reliably held in a working memory buffer during the delay period. Jacobsen reported that monkeys with prefrontal lesions involving the sulcus principalis were unable to remember the location of a baited well at short retention intervals. The Jacobsen finding provided a landmark observation for insight into the role of prefrontal cortex in organized behavior (Jacobsen, 1935). Subsequent research has shown that prefrontal spatial memory deficits are apparent at delays as short as 1 s (Funahashi, Bruce & Goldman-Rakic, 1993).

The delayed response deficit was initially interpreted to reflect a simple memory problem. However, animal research in the 1940’s revealed that a problem with the inhibition of extraneous inputs was a major contributor to the delayed response deficit. These findings led to the formulation of the distractibility hypothesis of prefrontal function Malmo, 1942, Bartus and Levere, 1977. The distractibility theory postulates that prefrontal patients are unable to suppress responses to irrelevant stimuli in a range of sensory motor and cognitive processes. Impairments in inhibitory control to sensory inputs are found in neurological patients with dorsolateral prefrontal damage and in schizophrenic patients with prefrontal hypometabolism on PET scanning, providing support for the prefrontal-distractibility hypothesis. However, successful performance on the delayed response task requires more than inhibitory control. Subjects must also selectively engage and integrate activity in different brain regions depending on task specific parameters. Single unit data in monkeys (Funahashi et al., 1993), electrophysiological data in normal controls and prefrontal lesioned patients (Chao & Knight, 1998), cerebral blood flow data in normal controls (Jonides, Smith, Koeppe, Mioshima & Mintun, 1993), and neural modelling (Cohen, Braver & O'Reilly, 1996) having shown that combined prefrontal-posterior association cortex activation is required to perform any task requiring a delay. Data from neurological patients has revealed that dorsolateral prefrontal cortex modulates excitatory pathways projecting into subregions of visual and auditory association cortex. Thus, it appears that prefrontal cortex exerts selective and parallel inhibitory and excitatory control to remote brain regions during a variety of behaviors. The net result of parallel and interactive prefrontal modulated neuronal activity results in the higher level functions attributed to prefrontal cortex.

In humans, dorsolateral prefrontal cortex is engaged in diverse cognitive processes including language, motor control, attention, and executive functions. Delayed response paradigms have elements in common with classic working memory tasks Baddeley, 1992a, Baddeley, 1992b. The main parallel between delayed response and working memory is the necessity to hold information in a temporary buffer. Working memory is well known to be dependent on prefrontal cortex Petrides et al., 1993a, Petrides et al., 1993b, Jonides et al., 1993, Knight, 1994. Although the prefrontal cortex is critical for integrative cognitive functions requiring working memory, it is unlikely that this capacity resides in specialized modules in prefrontal regions. More likely, the spectrum of cognitive capacities involving prefrontal cortex is supported by interactions in the extensive bi-directional connections between prefrontal cortex and numerous cortical, limbic, and subcortical regions Goldman-Rakic et al., 1984, Friedman and Goldman-Rakic, 1994.

Prefrontal cortex (particularly Brodmann areas 9 and 46) is well known to be involved in both sustained and phasic attention to environmental events (Stuss & Benson, 1986). Sustained attention and phasic orienting capacity have been examined in neurological patients with focal prefrontal lesions using behavioral and event-related potential (ERP) recording techniques. Neurophysiological impairments in these patients include problems with inhibitory control of sensory inputs Knight et al., 1989a, Knight et al., 1989b, Yamaguchi and Knight, 1990, Yamaguchi and Knight, 1991, deficits in selective and sustained attention Knight et al., 1981, Woods and Knight, 1986, Knight, 1991, and abnormalities in the detection of novel events Knight, 1984, Knight, 1996, Knight, 1997. The inability to inhibit irrelevant inputs and sustain attention, coupled with deficits in novelty detection, impairs the coding and the processing of discrete external events and may underlay the temporal order (Shimamura, Janowsky & Squire, 1990) and decision making impairments observed subsequent to prefrontal damage Shimamura, 1995, Shimamura et al., 1995. Similar to the role prefrontal cortex plays in regulating the interaction with the external world, this region is crucial for attention to and inhibitory control of internal mental representations engaged during working memory, employment of strategies, planning and decision-making Janowsky et al., 1989a, Janowsky et al., 1989b, Shimamura et al., 1995, Knight and Grabowecky, 1995, Stuss and Benson, 1984, Stuss and Benson, 1986 The inability to inhibit internal representations of previous responses which are no longer correct contributes to poor performance on the Wisconsin card sorting task (WCST) and the Stroop task Shimamura, 1995, Shimamura et al., 1995, Vendrell et al., 1995. In the WCST task subjects are required to change their criteria for sorting a deck of cards varying in shape or color. Patients with prefrontal damage are impaired at switching to a new sorting criteria and continue to incorrectly sort by the prior rule. This tendency to preseverate is viewed by cognitive theorists as a failure in inhibitory control of prior mental sets. Damage in prefrontal cortex also results in a failure in inhibition of reflexive saccadic eye movements Guitton et al., 1985, Pierrot-Deseillingny et al., 1991. The animal and human data supporting these contentions will be discussed.

Section snippets

Inhibition in animals

Inhibition of neural activity under prefrontal control has been reported in a variety of mammalian preparations. Net prefrontal inhibitory control of both subcortical (Edinger, Siegel & Troiano, 1975) and cortical regions has been documented Alexander et al., 1976, Skinner and Yingling, 1977. Galambos (1956) provided the first physiological evidence of an inhibitory auditory pathway in mammals with the description of the brainstem olivo-cochlear bundle. The olivo-cochlear bundle projects from

Inhibition in humans

The attention deficits and perseveration observed behaviorally in frontal patients have been linked to problems with inhibitory control of posterior sensory and perceptual mechanisms Lhermitte, 1986, Lhermitte et al., 1986. Early sensory gating deficits (20–50 ms), sustained attention problems (100–500 ms) and abnormalities in the phasic detection of novel events (250–500 ms) are all observed after prefrontal damage. ERPs are brain potentials that are time-locked to the occurrence of sensory,

Motor control and inhibition

Inhibitory modulation of sensory input is also important in motor control. Transmission through somatosensory afferents in under constant modulation. The predominant effect is inhibition of the ascending sensory paths. Gating of sensory inputs is reported at all levels of the neuraxis, from the segmental reflex to the primary cortical receptive zones MacKay and Crammond, 1989, Shin and Chapin, 1990a, Shin and Chapin, 1990b. There are two mechanisms for the control of this sensory input during

Selective attention and prefrontal cortex

In a seminal report, Hillyard, Hink, Schwent and Picton (1973) found that focussed attention to tones in one ear resulted in a systematic negative enhancement of evoked potentials to all stimuli in that ear. This enhancement onsets at about 50 ms post-stimulation and was shown to be sustained for at least 200 and 500 ms (Hansen & Hillyard, 1980). These electrophysiological results were critical to attention theorists. First, stimulus discriminability was shown to be dependent on the degree of

Prefrontal cortex and excitatory control

In addition to suppressing response to irrelevant stimuli, subjects must sustain neural activity in distributed brain regions in order to perform delay and working memory tasks. There is evidence of failure in excitatory control in patients with prefrontal damage. Prefrontal lesioned patients were tested on an auditory delayed-match-to-sample task. As noted above, prefrontal patients were behaviorally impaired by distractors and generated enhanced primary auditory cortex evoked responses to

Conclusions

The accumulated evidence from behavioral, electrophysiological and blood flow techniques supports the long held clinical view that prefrontal cortex is crucial for integrative behavior. The data has revealed the existence of both inhibitory and excitatory prefrontal control of distributed neural activity in posterior brain regions. The unique capacity of prefrontal cortex to simulataneouly modulate activity in multiple brain regions is paralleled by the enormous evolution of prefrontal cortex

Acknowledgements

This work was supported by the National Institute of Neurological Disorders and Stroke grants NS21135 and PO17778 to RTK, the Veterans Administration Medical Research Service and Medical Research Council of Canada (to WRS). Special thanks to Clay Clayworth for technical assistance in all phases of work.

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