EEG activities in the orbitofrontal cortex and dorsolateral prefrontal cortex during the development of morphine dependence, tolerance and withdrawal in rhesus monkeys

Investigating the activities of the prefrontal cortex (PFC) in the process of addiction is valuable for understanding the neural mechanism underlying the impairments of the PFC after drug abuse. However, limited data are obtained from primate animals and few studies analyze Electroencephalogram (EEG) in the gamma band, which plays an important role in cognitive functions. In addition, it is yet unclear whether drug abuse affects the orbitofrontal cortex (OFC) and dorsolateral PFC (DLPFC) - the two most important subregions of the PFC - in similar ways or not. The aim of this study is to address these issues. We recorded EEG in the OFC and DLPFC in three rhesus monkeys. All animals received a course of saline (NaCl 0.9%, 2 ml) injection (5 days) followed by 10 days of morphine injection (every 12 h), and then a further series of saline injection (7 days). A main finding in the present study was that morphine decreased EEG power in all frequency bands in a short period after injection in both the OFC and DLPFC in monkeys. And gamma power decreased not just in short period after morphine injection but lasted to 12 h after injection. Moreover, we found that although the changes in EEG activities in the OFC and DLPFC at 30-35 min after injection were similar, the DLPFC was more sensitive to the effect of morphine than the OFC. (c) 2005 Elsevier B.V. All rights reserved.

The effects of TMS over dorsolateral prefrontal cortex on trans-saccadic memory of multiple objects

Humans typically make several rapid eye movements (saccades) per second. It is thought that visual working memory can retain and spatially integrate three to four objects or features across each saccade but little is known about this neural mechanism. Previously we showed that transcranial magnetic stimulation (TMS) to the posterior parietal cortex and frontal eye fields degrade trans-saccadic memory of multiple object features (Prime, Vesia, & Crawford, 2008, Journal of Neuroscience, 28(27), 6938-6949; Prime, Vesia, & Crawford, 2010, Cerebral Cortex, 20(4), 759-772.). Here, we used a similar protocol to investigate whether dorsolateral prefrontal cortex (DLPFC), an area involved in spatial working memory, is also involved in trans-saccadic memory. Subjects were required to report changes in stimulus orientation with (saccade task) or without (fixation task) an eye movement in the intervening memory interval. We applied single-pulse TMS to left and right DLPFC during the memory delay, timed at three intervals to arrive approximately 100ms before, 100ms after, or at saccade onset. In the fixation task, left DLPFC TMS produced inconsistent results, whereas right DLPFC TMS disrupted performance at all three intervals (significantly for presaccadic TMS). In contrast, in the saccade task, TMS consistently facilitated performance (significantly for left DLPFC/perisaccadic TMS and right DLPFC/postsaccadic TMS) suggesting a dis-inhibition of trans-saccadic processing. These results are consistent with a neural circuit of trans-saccadic memory that overlaps and interacts with, but is partially separate from the circuit for visual working memory during sustained fixation.

Representation of motor habit in a sequence of repetitive reach and grasp movements performed by macaque monkeys: evidence for a contribution of the dorsolateral prefrontal cortex.

In the context of an autologous cell transplantation study, a unilateral biopsy of cortical tissue was surgically performed from the right dorsolateral prefrontal cortex (dlPFC) in two intact adult macaque monkeys (dlPFC lesioned group), together with the implantation of a chronic chamber providing access to the left motor cortex. Three other monkeys were subjected to the same chronic chamber implantation, but without dlPFC biopsy (control group). All monkeys were initially trained to perform sequential manual dexterity tasks, requiring precision grip. The motor performance and the prehension's sequence (temporal order to grasp pellets from different spatial locations) were analysed for each hand. Following the surgery, transient and moderate deficits of manual dexterity per se occurred in both groups, indicating that they were not due to the dlPFC lesion (most likely related to the recording chamber implantation and/or general anaesthesia/medication). In contrast, changes of motor habit were observed for the sequential order of grasping in the two monkeys with dlPFC lesion only. The changes were more prominent in the monkey subjected to the largest lesion, supporting the notion of a specific effect of the dlPFC lesion on the motor habit of the monkeys. These observations are reminiscent of previous studies using conditional tasks with delay that have proposed a specialization of the dlPFC for visuo-spatial working memory, except that this is in a different context of "free-will", non-conditional manual dexterity task, without a component of working memory.

Satiation attenuates BOLD activity in brain regions involved in reward and increases activity in dorsolateral prefrontal cortex: an fMRI study in healthy volunteers

BACKGROUND: Neural responses to rewarding food cues are significantly different in the fed vs. fasted (>8 h food-deprived) state. However, the effect of eating to satiety after a shorter (more natural) intermeal interval on neural responses to both rewarding and aversive cues has not been examined. OBJECTIVE: With the use of a novel functional magnetic resonance imaging (fMRI) task, we investigated the effect of satiation on neural responses to both rewarding and aversive food tastes and pictures. DESIGN: Sixteen healthy participants (8 men, 8 women) were scanned on 2 separate test days, before and after eating a meal to satiation or after not eating for 4 h (satiated vs. premeal). fMRI blood oxygen level-dependent (BOLD) signals to the sight and/or taste of the stimuli were recorded. RESULTS: A whole-brain cluster-corrected analysis (P < 0.05) showed that satiation attenuated the BOLD response to both stimulus types in the ventromedial prefrontal cortex (vmPFC), orbitofrontal cortex, nucleus accumbens, hypothalamus, and insula but increased BOLD activity in the dorsolateral prefrontal cortex (dlPFC; local maxima corrected to P ≤ 0.001). A psychophysiological interaction analysis showed that the vmPFC was more highly connected to the dlPFC when individuals were exposed to food stimuli when satiated than when not satiated. CONCLUSIONS: These results suggest that natural satiation attenuates activity in reward-related brain regions and increases activity in the dlPFC, which may reflect a "top down" cognitive influence on satiation. This trial was registered at clinicaltrials.gov as NCT02298049.

Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia

Schizophrenia is likely to be a consequence of serial alterations in a number of genes that, together with environmental factors, will lead to the establishment of the illness. The dorsolateral prefrontal cortex (Brodmann`s Area 46) is implicated in schizophrenia and executes high functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts, correct social behavior and personality expression. We performed a comparative proteome analysis using two-dimensional gel electrophoresis of pools from 9 schizophrenia and 7 healthy control patients` dorsolateral prefrontal cortex aiming to identify, by mass spectrometry, alterations in protein expression that could be related to the disease. In schizophrenia-derived samples, our analysis revealed 10 downregulated and 14 upregulated proteins. These included alterations previously implicated in schizophrenia, such as oligodendrocyte-related proteins (myelin basic protein and transferrin), as well as malate dehydrogenase, aconitase, ATP synthase subunits and cytoskeleton-related proteins. Also, six new putative disease markers were identified, including energy metabolism, cytoskeleton and cell signaling proteins. Our data not only reinforces the involvement of proteins previously implicated in schizophrenia, but also suggests new markers, providing further information to foster the comprehension of this important disease. (C) 2008 Elsevier Ltd. All rights reserved.

Proteome analysis of human dorsolateral prefrontal cortex using shotgun mass spectrometry

The prefrontal cortex executes important functions such as differentiation of conflicting thoughts, correct social behavior and personality expression, and is directly implicated in different neurodegenerative diseases. We performed a shotgun proteome analysis that included IEF fractionation, RP-LC, and MALDI-TOF/TOF mass spectrometric analysis of tryptic digests from a pool of seven human dorsolateral prefrontal cortex protein extracts. In this report, we present a catalog of 387 proteins expressed in these samples, identified by two or more peptides and high confidence search scores. These proteins are involved in different biological processes such as cell growth and/or maintenance, metabolism/energy pathways, cell communication/signal trarisduction, protein metabolism, transport, regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolism, and immune response. This analysis contributes to the knowledge of the human brain proteome by adding sample diversity and protein expression data from an alternative technical approach. It will also aid comparative studies of different brain areas and medical conditions, with future applications in basic and clinical research.

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation

Transcranial magnetic stimulation has evolved into a powerful neuroscientific tool allowing to interfere transiently with specific brain functions. In addition, repetitive TMS (rTMS) has long-term effects (e.g. on mood), probably mediated by neurochemical alterations. While long-term safety of rTMS with regard to cognitive functioning is well established from trials exploring its therapeutic efficacy, little is known on whether rTMS can induce changes in cognitive functioning in a time window ranging from minutes to hours, a time in which neurochemical effects correlated with stimulation have been demonstrated. This study examined effects of rTMS on three measures of executive function in healthy subjects who received one single rTMS session (40 trains of 2 s duration 20 Hz stimuli) at the left dorsolateral prefrontal cortex (DLPFC). Compared to a sham condition one week apart, divided attention performance was significantly impaired about 30-60 min after rTMS, while Stroop-interference and performance in the Wisconsin Card Sorting Test was unaffected after rTMS. Repetitive TMS of the left DLPFC, at stimulation parameters used in therapeutic studies, does not lead to a clinically relevant impairment of executive function after stimulation. However, the significant effect on divided attention suggests that cognitive effects of rTMS are not limited to the of acute stimulation, and may possibly reflect known neurochemical alterations induced by rTMS. Sensitive cognitive measures may be useful to trace those short-term effects of rTMS non-invasively in humans.

Inhibitory control of the human dorsolateral prefrontal cortex during the anti-saccade paradigm--a transcranial magnetic stimulation study

In the anti-saccade paradigm, subjects are instructed not to make a reflexive saccade to an appearing lateral target but to make an intentional saccade to the opposite side instead. The inhibition of reflexive saccade triggering is under the control of the dorsolateral prefrontal cortex (DLPFC). The critical time interval at which this inhibition takes place during the paradigm, however, is not exactly known. In the present study, we used single-pulse transcranial magnetic stimulation (TMS) to interfere with DLPFC function in 15 healthy subjects. TMS was applied over the right DLPFC either 100 ms before the onset of the visual target (i.e. -100 ms), at target onset (i.e. 0 ms) or 100 ms after target onset (i.e. +100 ms). Stimulation 100 ms before target onset significantly increased the percentage of anti-saccade errors to both sides, while stimulation at, or after, target onset had no significant effect. All three stimulation conditions had no significant influence on saccade latency of correct or erroneous anti-saccades. These findings show that the critical time interval at which the DLPFC controls the suppression of a reflexive saccade in the anti-saccade paradigm is before target onset. In addition, the results suggest the view that the triggering of correct anti-saccades is not under direct control of the DLPFC.

Dorsolateral and ventromedial prefrontal cortex orchestrate normative choice.

Humans are noted for their capacity to over-ride self-interest in favor of normatively valued goals. We examined the neural circuitry that is causally involved in normative, fairness-related decisions by generating a temporarily diminished capacity for costly normative behavior, a 'deviant' case, through non-invasive brain stimulation (repetitive transcranial magnetic stimulation) and compared normal subjects' functional magnetic resonance imaging signals with those of the deviant subjects. When fairness and economic self-interest were in conflict, normal subjects (who make costly normative decisions at a much higher frequency) displayed significantly higher activity in, and connectivity between, the right dorsolateral prefrontal cortex (DLPFC) and the posterior ventromedial prefrontal cortex (pVMPFC). In contrast, when there was no conflict between fairness and economic self-interest, both types of subjects displayed identical neural patterns and behaved identically. These findings suggest that a parsimonious prefrontal network, the activation of right DLPFC and pVMPFC, and the connectivity between them, facilitates subjects' willingness to incur the cost of normative decisions.

Dissociation of egocentric and allocentric spatial processing in prefrontal cortex

Monkeys with lesions of areas 9 and 46 performed three variants of the spatial delayed response (SDR) task. There were no impairments in allocentric spatial memory in which geometrical relationships between environmental cues were used to identify spatial location; thus, memory of a 3D environmental map is intact. In contrast, there were severe impairments in egocentric spatial memory guided by visual or tactile cues that monkeys can relate to their viewing perspective during testing. These results strongly suggest that dorsolateral prefrontal cortex selectively mediates spatial memory tasks that are solved by referencing the location of targets to the body's orientation. (C) 2003 Lippincott Williams Wilkins.

Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation.

The Iowa gambling task (IGT) is one of the most influential behavioral paradigms in reward-related decision making and has been, most notably, associated with ventromedial prefrontal cortex function. However, performance in the IGT relies on a complex set of cognitive subprocesses, in particular integrating information about the outcome of choices into a continuously updated decision strategy under ambiguous conditions. The complexity of the task has made it difficult for neuroimaging studies to disentangle the underlying neurocognitive processes. In this study, we used functional magnetic resonance imaging in combination with a novel adaptation of the task, which allowed us to examine separately activation associated with the moment of decision or the evaluation of decision outcomes. Importantly, using whole-brain regression analyses with individual performance, in combination with the choice/outcome history of individual subjects, we aimed to identify the neural overlap between areas that are involved in the evaluation of outcomes and in the progressive discrimination of the relative value of available choice options, thus mapping the two fundamental cognitive processes that lead to adaptive decision making. We show that activation in right ventromedial and dorsolateral prefrontal cortex was predictive of adaptive performance, in both discriminating disadvantageous from advantageous decisions and confirming negative decision outcomes. We propose that these two prefrontal areas mediate shifting away from disadvantageous choices through their sensitivity to accumulating negative outcomes. These findings provide functional evidence of the underlying processes by which these prefrontal subregions drive adaptive choice in the task, namely through contingency-sensitive outcome evaluation.

Prefrontal cortex modulation using transcranial DC stimulation reduces alcohol craving: A double-blind, sham-controlled study

Background: Functional neuroimaging studies have shown that specific brain areas are associated with alcohol craving including the dorsolateral prefrontal cortex (DLPFC). We tested whether modulation of DLPFC using transcranial direct current stimulation (tDCS) could alter alcohol craving in patients with alcohol dependence while being exposed to alcohol cues. Methods: We performed a randomized sham-controlled study in which 13 subjects received sham and active bilateral tDCS delivered to DLPFC (anodal left/cathodal right and anodal right/cathodal left). For sham stimulation, the electrodes were placed at the same positions as in active stimulation; however, the stimulator was turned off after 30 s of stimulation. Subjects were presented videos depicting alcohol consumption to increase alcohol craving. Results: Our results showed that both anodal left/cathodal right and anodal right/cathodal left significantly decreased alcohol craving compared to sham stimulation (p < 0.0001). In addition, we found that following treatment, craving could not be further increased by alcohol cues. Conclusions: Our findings showed that tDCS treatment to DLPFC can reduce alcohol craving. These findings extend the results of previous studies using noninvasive brain stimulation to reduce craving in humans. Given the relatively rapid suppressive effect of tDCS and the highly fluctuating nature of alcohol craving, this technique may prove to be a valuable treatment strategy within the clinical setting. (C) 2007 Elsevier Ireland Ltd. All rights reserved.