User:Soph Elizabeth/sandbox

The dorsolateral prefrontal cortex (DL-PFC or DLPFC) constitutes a portion of the prefrontal cortex (PFC), along with the inferior prefrontal cortex and the medial frontal cortex. According to Brodmann's map of the cortex, the DLPFC is roughly equivalent to Broadmann areas 9 and 46. These regions mainly receive their blood supply from the middle cerebral artery.

Associated Neurotransmitters and Connections
With respect to neurotransmitter systems, there is evidence that dopamine plays a particularly important role in DLPFC. Dopaminergic cells in the tegmentum provide significant input to the regions of the PFC and the majority of neuroscience research supports the notion of dopamine having an important role in effective PFC functioning. Experiencing a disturbance in dopamine transmission in the PFC leads to abnormal activity and disrupts the performance of its primary functions, such as working memory.

The DLPFC is connected to a variety of brain areas; however, it receives its main inputs from reciprocal connections with the posterior parietal areas and the superior temporal sulcus. In addition, the DLPFC has extensive connections to regions to which the posterior parietal cortex also projects, including the cingulate cortex, basal ganglia, and superior colliculus. Thus, investigating the relation between the DLPFC and the posterior parietal cortex is hypothesized to lead to a better understanding of the region's function. Lastly, a circuitry believed to participate in working memory (WM) exists between the DLPFC, the striatum, and the basal ganglia. While projecting to the striatum, the DLPFC receives inputs back from the basal ganglia via the thalamus.

Proposed Function of the DLPFC
The DLPFC is critically involved in high-level cognitive processes  and as previously mentioned, a well established primary function of this region is working memory. Extensive research (most of which involved the sensory modality of vision) has investigated the role of the DLPFC in various working memory tasks in which higher cognitive functions including thinking, reasoning, decision making, and language comprehension, is necessary. Over the last half decade, a considerable amount of research has provided evidence for the involvement of the DLPFC in both spatial and non-spatial working memory tasks. Goldman-Rakic was the first to propose that this brain region is the location for the maintenance and rehearsal of spatial information in working memory. Since the initial proposal, extensive animal and human studies have been conducted in order to support the role of the DLPFC as a spatial information processor. During the same time period, research exploring the involvement of the DLPFC in non-spatial working memory tasks was advancing. After reports of DLPFC activation during memory tasks in which spatial characteristics were not essential for correct performance, the search for evidence supporting DLPFC as a non-spatial information processor drastically increased during the early 1990’s.

Spatial Working Memory
In the 1930’s, it had been reported that monkeys with bilateral lesions of the prefrontal cortex were impaired in tasks involving spatial cues. Since that time, countless animal studies have been conducted to determine precise brain regions responsible for processing and responding to spatial cues. In the 1960’s, preliminary research on the role of the different PFC regions in spatial working memory began and in 1976, Bauer further investigated the extent to which the DLPFC in monkeys influenced spatial information processing. Localized cooling of the DLPFC was performed in order to produce functional inactivation of the region before the monkeys were tested on a delayed response task, a well known assessment of short-term memory of spatial visual information. In the delayed response task, the monkeys were first presented with a randomly positioned light cue and were trained to press a button in response to the cue which started the delay period. At the end of the delay, response buttons were all illuminated and the monkey received a food reward for pressing the button positioned in the same location as the onset cue. As the delay period was increased, the animals showed a significant decrease in correct responses. The researcher concluded that inactivation of the DLPFC produced deficits in tasks involving spatial information that must be held in working memory over a period of delay and thus, a function of this region was spatial working memory.

Researchers began to investigate the function of the DLPFC in humans by the use of brain imaging. Data from preliminary PET research indicated that the right lateral prefrontal cortex in humans is involved in maintaining spatial information for short periods of time. Later, in 1996, Owen, Evans and Petrides conducted a PET study further investigating the contribution of the frontal cortex in tasks involving spatial working memory. The researchers hypothesized that the function of the DLPFC in humans would parallel that found in monkeys, and thus would prove to be the prefrontal region required to monitor and manipulate spatial information in working memory. While in the scanner, participants were presented with three circle stimuli, one after another, in random locations on the computer screen. After a period of delay, eight circles appeared on the screen simultaneously and the participants were instructed to indicate (in any order) which of the three circles were in the identical locations of the three stimuli presented before the delay. The participants were then subjected to another task assessing spatial working memory in which they were instructed to avoid responding to the stimuli locations that had already been attended to. The two tasks involved the monitoring of stimuli location, thus the participants’ working memory was actively managing spatial information. The PET scans indicated that greater cerebral blood flow was found in the mid-DLPFC during both of the spatial monitoring tasks. The researchers concluded that the DLPFC in humans is critically involved in spatial working memory due to the increased activation of the region during tasks that require responding to spatial cues.

Non-Spatial Working Memory
In the late 1960’s, multiple studies found that interrupting the activity of the DLPFC, by means of prefrontal lesions or electrical stimulation, resulted in deficits of tasks in which short-term memory of visual information was required. However, correct performance on such tasks did not ultimately depend on the spatial characteristics of the information, suggesting that the DLPFC is additionally activated for non-spatial working memory. Michael Petrides conducted extensive research throughout the 1980’s, 90’s, and into the 2000’s on this proposed function of the DLPFC in order to challenge the traditional view that damage to the DLPFC would only impair spatial cognition. In 1991, Petrides investigated whether lesions to the mid-DLPFC would lead to impairment in ability to recall which stimulus from a set of objects had previously been chosen, a task that did not involve monitoring spatial information. The researcher hoped to achieve a better understanding of the nature of impairments that result from frontal-lobe lesions. Through extensive practice, Petrides trained monkeys to recall which stimulus from a set of objects had previously been chosen. During the presentation trial, the monkey was presented with three objects and was allowed to select one of them in order to obtain a food reward. Then on the test trial, the monkey was presented with two objects: the object previously selected as well as one of the other objects that had not been selected. In order to receive a food reward on the test trial, the monkey was to select the object that had not previously been chosen. After lesions to the mid-DLPFC, monkeys exhibited striking impairments in the task and were unable to correctly recall which stimulus had been previously chosen. The researcher concluded that the DLPFC is crucially involved in the monitoring of an animal’s choices and that this high-level cognitive function did not rely on spatial information.

Four years later, Petrides conducted a series of experiments further investigating the role of the DLPFC when monkeys were to monitor their selection of stimuli. There was limited research demonstrating that after lesions to the DLPFC, monkeys would be severely impaired in non-spatial tasks of working memory. To account for this lack of information, and to provide additional support of his earlier findings, Petrides examined the monkeys’ ability to monitor visual stimuli that were considered to be non-spatial in nature. The purpose of the study was to provide evidence for the involvement of the DLPFC on working memory tasks based entirely on non-spatial information and not spatial coding. The experiment included self-ordered tasks (identical to the procedures in the 1991 study), and externally ordered tasks. In the later task, the animal was first subjected to two presentation trials, each of which displayed a different single stimulus. During the test trial, the monkey was presented with three stimuli and would receive a food reward if the novel object was chosen. In both types of tasks, the stimuli were arranged in variation so that spatial coding of the stimuli would not aid the animal in performing a correct response. Solution of these tasks was therefore based entirely on memory. The results of the study were in accordance with the researcher’s earlier work: the monkeys had severe impairments on non-spatial memory tasks after lesions to the DLPFC. In addition, the monkeys were retested three years later to see if the impairment persisted and results revealed that the deficits were long-lasting. This experiment was influential in demonstrating that damage to the DLPFC impaired monkeys on self-ordered and externally-ordered tasks of non-spatial working memory and that the deficits would endure.

The frontal cortex was first proposed to have a role in monitoring self-generated choices in humans by Michael Petrides and Brenda Milner in 1982. While working with patients with frontal lobe damage, the researchers noted that a participant’s performance on tasks that required the monitoring of previous selections of stimuli within working memory was strikingly impaired. These observations, along with the results from lesion studies of self-ordered tasks in monkeys, influenced an investigation of the role of human prefrontal areas in monitoring the order of stimuli in working memory. By use of fMRI, Amiez and Petrides sought to determine whether the mid-DLPFC was significantly activated when healthy participants were to attend to the order of a short sequence of visual stimuli, demonstrating the process of working memory. In the study, participants were scanned while performing a serial-order memory task in which they first were presented with a sequence of four visual stimuli. This was followed by a test trial that simultaneously displayed two of the stimuli presented earlier. The subject was instructed to indicate which of the two stimuli occurred earlier in the sequence. The task was considered non-spatial in nature because the participants had to monitor the precise order of stimuli and not the physical location or characteristics of the stimuli. The fMRI scans indicated that activity in the mid-DLPFC was significantly increased when participants were monitoring the serial order of stimuli in working memory. The results of the study provide evidence that the human DLPFC is critically involved in monitoring non-spatial information in working memory.

Aging and the Functioning of the DLPFC
It is well documented that the deterioration of the frontal lobes occurs earlier and more severely than other brain areas in healthy aging adults and current models propose that this trend in deterioration is responsible for common cognitive changes related to age. Autopsy studies provide evidence that the DLPFC is particularly sensitive to age effects because of the region’s significant decreases in brain weight, cortical thickness, and number of large neurons. Higher cognitive abilities and working memory are associated with the activity of the DLPFC; such executive functions would be negatively affected by the process of aging due to the prominent decay occurring in the DLPFC. MacPherson and associates examined the effects of healthy adult aging on tasks that required working memory (and therefore the activation of the DLPFC), which included: the Wisconsin Card Sorting Task, Self-Ordered Pointing Task, and Delayed-Response Task. Age effects were observed on all three of the tasks; the oldest group of participants performed significantly worse than the two younger groups on the two later tasks, and in addition, the oldest group performed significantly more poorly on the Wisconsin Card Sorting Task compared to the youngest group of participants. The researchers concluded that higher cognitive functions mediated by the DLPFC are subject to the effects of aging in healthy adults.