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Cognitive N140 electrogenesis and concomitant 40 Hz synchronization in mid-dorsolateral prefrontal cortex (area 46) identified in non-averaged human brain potentials.

The mid-dorsolateral prefrontal area 46 has working memory functions for putting current cognitive processing into context and for updating relevant information on a trial-by-trial basis. Using non-averaged human brain responses to a target finger stimulus attended by the subject, we identified the cognitive prefrontal N140 electrogenesis with the Z method which numerically assesses the detailed consistency between scalp topographies of any single response and a grand average template. The cognitive N140 was present between 100 and 180 ms at the scalp contralateral to the attended target finger stimulus. Control responses to physically identical finger stimuli that were ignored by the subject did not elicit a prefrontal N140. In brain mapping the N140 focus was located 30-80 mm from scalp midline, and 50-60 mm in front of the vertex (Cz) coronal plane of the head. The data were consistent with recently disclosed anatomical locations of area 46 and they further document its interindividual variations in brain-to-scalp relationship. N140, is thought to manifest cortico-cortical activation from the posterior parietal area 7b which generates the cognitive P100 electrogenesis that precedes N140 in the target response. At the prefrontal site, the non-averaged EEG showed desynchronized 40 Hz oscillations, but these became transiently phase-locked in conjunction with the cognitive N140 excitatory effect. This seems in line with the Traub model suggesting that excitation of certain cortical inhibitory interneurons generates doublet firings which will pace the spiking of pyramidal neurons so as to promote synchronization at about 40 Hz. These results complement our recent finding that P300 inhibition conversely disrupts on-going 40 Hz phase-locking ('binding'). Considering the marked trial-to-trial variations in timing of the cortical cognitive processes, such physiological relationships between target response components and 40 Hz dynamics could only be uncovered by studying non-averaged single responses.

Adult↗

The role of the right dorsolateral prefrontal cortex in visual change awareness.

Recently, the neural correlates of change detection vs change blindness have been investigated using fMRI. Results revealed that conscious perception of change is associated with enhanced activity in a neural network comprising the parietal (bilateral) and right dorsolateral prefrontal (DLPF) cortex. Here, by means of repetitive transcranial magnetic stimulation (rTMS), we unveil the causal role of the right DLPF cortex in perceiving changes. When rTMS was applied to this area, change perception was impaired as compared to left DLPF rTMS and sham stimulation. This result is important as it shows, for the first time, that conscious change perception is associated with normal activity in the right DLPF cortex. Our findings are in agreement with a recent view emphasizing the role of frontal areas, in addition to classical ventral and dorsal pathways, in visual awareness.

Adult↗

Induction of errors in a delayed response task by repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.

We used repetitive transcranial magnetic stimulation to study the function of the dorsolateral frontal cortex in a delayed response task in 10 normal volunteers. Unilateral stimulation of right or left prefrontal cortex during the delay period between instruction and execution cues led to a significantly greater number of response errors than stimulation of motor cortex or in unstimulated trials. Repetitive transcranial stimulation of appropriate intensity and frequency seems to disrupt the function of mnemonic cells in the prefrontal cortex and is useful for the study of the role of the prefrontal cortex in short-term motor memory.

Adult↗

A subsequent-memory effect in dorsolateral prefrontal cortex.

The importance of brain regions for long-term memory encoding has been examined by comparison of encoding-related neural activity on trials in which successful recollection subsequently occurred to the encoding-related activity on trials in which successful recollection did not occur. We applied similar analyses to event-related functional magnetic resonance imaging (fMRI) data to explore the relative roles of dorsolateral and ventrolateral prefrontal cortex (PFC) regions during specific components of a working-memory (WM) maintenance task. The results of this study indicated that increases in dorsolateral PFC activity during encoding was related to subsequent retrieval-success. These results lend support to the hypothesis that ventrolateral PFC mediates a limited-capacity WM buffer that supports rehearsal maintenance functions while dorsolateral PFC mediates WM organization functions that accommodate the capacity limits of WM maintenance.

Adult↗

Topographic studies on visual neurons in the dorsolateral prefrontal cortex of the monkey.

The topographic distribution and organization of visual neurons in the prefrontal cortex was examined in alert monkeys. The animal was trained to fixate straight ahead onto a tinty, dim light spot. While he was fixating, we presented a stationary second light spot (RF spot) at various locations in the visual field and examined unit responses of the prefrontal neurons to the RF-spot stimulus. Many prefrontal neurons, especially those located in the relatively superficial layers of the cortex, responded with a phasic and/or tonic activation to the RF spot illuminating a limited extent of the visual field, a receptive field (RF) being so determined. The visual neurons were found to be widely distributed in the prearcuate and inferior dorsolateral areas. One hemisphere mainly represented the contralateral visual field. According to the location of the neurons in these areas, their visual properties varied with respect to RF eccentricity from the fovea and in size. The neurons located in the lateral part of the areas and close to the inferior arcuate sulcus had relatively small RFs representing the foveal and parafoveal regions. When the recording site was moved medially, the RFs became eccentric from the fovea and were larger. Then, the neurons located between the caudal end of the principal sulcus and the arcuate sulcus had RFs with a considerable eccentricity. The size of the RF became progressively larger for anteriorly located neurons and this occurred generally without a change in RF eccentricity. The visual neurons were not organized on a regular pattern in the cortex with regard to their RF direction (vector angle) from the foveal region. From these observations, we conclude, first, that the prearcuate and inferior dorsolateral areas of the prefrontal cortex are functionally differentiated so that the lateral area's function is related to central vision, while that of the medial area to ambient vision. Second, the RF representation on the cortex with loss of the vector relation may generate an interaction between separate objects in visual space and may subserve the control of attention performance.

Animals↗

High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients.

Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in major depression. In order to investigate the therapeutic efficacy of rTMS in psychotic patients, 12 participants (four women, eight men) with schizophrenia according to DSM-IV criteria, aged 25 to 63 years (mean (+/-s.d) 40.4+/-11.0), were enrolled in the study. Following a double-blind crossover design, patients were treated at random with 2 weeks of daily left prefrontal rTMS (20 2s 20 Hz stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. The Brief Psychiatric Rating Scale decreased under active rTMS (p <0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly. Prefrontal rTMS might be effective in the non-pharmacological treatment of psychotic patients.

Adult↗

Impairment of social perception associated with lesions of the prefrontal cortex.

OBJECTIVE: Behavioral and social impairments have been frequently reported after damage to the prefrontal cortex in humans. This study evaluated social perception in patients with prefrontal cortex lesions and compared their performance on a social perception task with that of healthy volunteers. METHOD: Thirty-three patients with prefrontal cortex lesions and 31 healthy volunteers were tested with the Interpersonal Perception Task. In this task, subjects viewed videotaped social interactions and relied primarily on nonverbal cues to make interpersonal judgments, such as determining the degree of intimacy between two persons depicted in the videotaped scene. Patients with prefrontal cortex lesions were classified according to lesion involvement of specific regions, including the orbitofrontal cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex. RESULTS: Relative to the comparison subjects, patients whose lesions involved the orbitofrontal cortex demonstrated impaired social perception. Contrary to predictions, patients with lesions in the dorsolateral prefrontal cortex also showed deficits in using social cues to make interpersonal judgments. All patients, particularly those with lesions in the dorsolateral prefrontal cortex, showed poorer insight into their deficits, relative to healthy volunteers. CONCLUSIONS: These findings of deficits in social perception after damage to the orbitofrontal cortex extend previous clinical and experimental evidence of damage-related impairment in other aspects of social cognition, such as the ability to accurately evaluate emotional facial expressions. In addition, the results suggest that the dorsolateral prefrontal cortex is recruited when inferences about social interactions are made on the basis of nonverbal information.

Brain Injuries↗

Properties and distribution of auditory neurons in the dorsolateral prefrontal cortex of the alert monkey.

In alert monkeys, some prefrontal neurons located in the superior dorsolateral area were activated to acoustic stimuli delivered in a restricted range of directions with respect to the animal's head. The effective direction was usually contralateral to the animal. The function of the auditory neurons in connection to that of the visual ones, which are commonly found in the prefrontal cortex, is discussed.

Acoustic Stimulation↗

Role of the dorsolateral prefrontal cortex in organizing visually guided behavior.

Unit activity was recorded in the prefrontal cortex of rhesus monkeys during performance of a delayed task with two motor responses, a saccade and an arm movement, to a complex pattern of auditory and visual stimuli. The peculiarity of the paradigm was that onset of the different sensory stimuli, orienting saccade and arm movement, were dissociated in time and occurred at prefixed time intervals. Two hundred and sixteen task-related units were recorded. The data show that the dorsolateral part of the prefrontal cortex plays a crucial role in temporal organization of visually guided behaviour. This cortical area contains the neural substrate of an encoding strategy for remembered or current events and objects in the behavioural surround that are not, as yet, foveated. This encoding mechanism subserves a particular cognitive process. Whether events or objects are, or are not, encoded depends on their significance for future behaviour. While foveation deletes their neural trace, it activates a class of cells that appear involved in the preparation of arm movements towards the foveated region. The destruction of these two complementary mechanisms would disrupt the organism's capacity to integrate temporally and spatially discontinuous information for performance of goal-directed acts.

Animals↗

Dorsolateral prefrontal cortex contribution to abnormalities of the P300 component of the event-related potential in schizophrenia.

Abnormalities of the P300 component of the event-related potential are a common finding in schizophrenia. It seems possible that the dysfunction in the dorsolateral prefrontal (DLPF) region that has been reported in schizophrenia contributes to this finding. To explore this possibility, we calculated the relationship between, on the one hand, P300 latency and amplitude and, on the other hand, the degree of DLPF atrophy (as measured by magnetic resonance imaging) and metabolic activity during an attentional task (as measured by positron emission tomography). Seventeen schizophrenia patients with a brief duration of illness and minimal exposition to treatment and 25 healthy controls were studied. Patients exhibited significantly lower metabolic activity in the DLPF region, but they did not show cortical atrophy. P300 amplitude was also significantly reduced in the schizophrenia patients compared with the controls. Right DLPF region metabolic activity correlated significantly with P300 amplitude. This pattern remained after partialling out the influence of activity in the hippocampus, superior temporal gyrus and parietal lobe. It is therefore suggested that the prefrontal cortex could be implicated in the P300 amplitude reduction in schizophrenia.

Adult↗

Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory.

OBJECTIVE: Adult first-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness, demonstrate working memory (WM) impairments, and manifest alterations in dorsolateral prefrontal cortical (DLPFC) function during WM. Because substantially less is known about these phenotypes in adolescent subjects we sought to demonstrate that young relatives of persons with schizophrenia manifest impaired WM and altered prefrontal activation. METHODS: Participants were 21 non-psychotic, unmedicated first-degree relatives of persons with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type and 24 unmedicated controls, recruited from the community and hospitals in metropolitan Boston (ages 13-28). We compared groups on an auditory WM task with interference prior to scanning and used functional magnetic resonance imaging (fMRI) to compare groups while performing visual 2-back WM and control vigilance tasks. Blood oxygen level dependent signal change was measured using two whole-brain gradient echo EPI pulse acquisitions (21 contiguous, 5mm axial slices), acquired on a Siemens 1.5T MR scanner. Data were analyzed using Statistical Parametric Mapping-99. RESULTS: The high risk subjects were significantly impaired on the auditory WM task, had significantly greater Phobic Anxiety, and marginally greater Psychoticism than controls on the Symptom Checklist-90-Revised, and showed significantly greater task-elicited activation in the right DLPFC (BA 46). Psychopathology, IQ, and in-scanner WM performance did not account for group differences in brain activation. CONCLUSIONS: Data support a physiological difference (an exaggerated fMRI response) in DLPFC in adolescents at genetic risk for schizophrenia, independent of psychosis. Future work can study the relationship of these measures to possible onset of schizophrenia.

Adolescent↗

Age-related deficits in generation and manipulation of mental images: II. The role of dorsolateral prefrontal cortex.

The authors investigated neural substrates of age-related declines in mental imagery. Healthy adult participants (ages 19 to 77) performed a series of visual-spatial mental imagery tasks that varied in apparent difficulty and involved stimuli of varying graphic complexity. The volumes of the dorsolateral frontal cortex (DLPFC) and posterior visual processing areas were estimated from magnetic resonance imaging scans. The volume of the DLPFC and the fusiform cortex, working-memory capacity, and performance on the tasks involving image generation and manipulation were significantly reduced with age. Further analyses suggested that age-related deficits in performance on mental imagery tasks may stem in part from age-related shrinkage of the prefrontal cortex and age-related declines in working memory but not from age-related slowing of sensorimotor reaction time. The volume of cortical regions associated with modality-specific visual information processing did not show a consistent relationship with specific mental imagery processes.

Adult↗

Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation.

Frontal lobe activity during pain is generally linked to attentional processing. We addressed the question of whether 'bottom-up' processing and 'top-down' modulation of nociceptive information dissociate anatomically within the frontal lobe by using PET scanning during painful thermal stimulation of normal and capsaicin-treated skin. We showed recently that pain following normally non-painful heat stimuli on chemically irritated skin (heat allodynia) uniquely engages extensive areas of the bilateral dorsolateral prefrontal (DLPFC), ventral/orbitofrontal (VOFC) and perigenual anterior cingulate (ACC) cortices. Here, we applied principal component analysis (PCA) and multiple regression analysis to study the covariance structure of the volumes of interest (VOI) activated specifically during heat allodynia in 14 male healthy subjects and evaluated the relationship of these VOI to ratings of pain intensity and affect. Results yielded a primary principal component (PC) that correlated positively with intensity and unpleasantness and accounted for activity in the medial thalamus, bilateral anterior insula, ventral striatum, perigenual ACC and bilateral VOFC. Activities in the right and left DLPFC loaded on separate PC and correlated negatively with perceived intensity and unpleasantness. The inter-regional correlation of midbrain and medial thalamic activity was significantly reduced during high left DLPFC activity, suggesting that its negative correlation with pain affect may result from dampening of the effective connectivity of the midbrain-medial thalamic pathway. In contrast, right DLPFC activity was associated with a weakened relationship of the anterior insula with both pain intensity and affect. We propose that the DLPFC exerts active control on pain perception by modulating corticosubcortical and corticocortical pathways.

Adult↗

Activity in ventrolateral and mid-dorsolateral prefrontal cortex during nonspatial visual working memory processing: evidence from functional magnetic resonance imaging.

Whole-brain functional magnetic resonance imaging was used to study five healthy human subjects while they performed two nonspatial visual working memory tasks and one control task. In the first memory task, the subjects were required to view a sequence of three pattern stimuli, randomly selected from a familiar set of four stimuli, and then identify which one of three simultaneously presented stimuli was the one that had not been presented in the previous array. In the other task, the subjects were required to observe an identical sequence of three randomly selected pattern stimuli and then to respond by selecting those same stimuli in the order presented. In comparison to a baseline control task, increases in signal intensity were observed, bilaterally, in the mid-dorsolateral frontal cortex and in the right ventrolateral frontal cortex in both memory tasks. When the two tasks were compared directly, however, the first memory task, which had the higher monitoring requirement, yielded significantly greater signal intensity changes in area 9/46 of the right mid-dorsolateral frontal cortex. These results provide further evidence for the precise functional contribution made by the mid-dorsolateral frontal cortex in visual working memory tasks and concur closely with findings in nonhuman primates.

Adult↗

The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task.

Research indicates that norepinephrine enhances the working memory functions of the prefrontal cortex (PFC) through actions at post-synaptic, alpha-2A adrenoceptors. The current study examined the effects of the alpha-2A adrenoreceptor agonist, guanfacine (0.7 mg/kg, i.m.), compared to saline on SPECT measures of regional cerebral blood flow (rCBF) in monkeys performing a spatial working memory task. Animals were infused with the SPECT blood flow tracer, Tcm-99m ECD, through an indwelling intravenous catheter while performing the working memory task. Guanfacine treatment significantly improved cognitive performance of the working memory task, and significantly increased rCBF values in the dorsolateral PFC, the brain region most tightly associated with performance of spatial working memory tasks. In contrast, guanfacine had no significant effect on rCBF in the superior temporal cortex, an auditory association area unrelated to task performance. These data are consistent with the hypothesis that alpha-2A adrenoceptor stimulation preferentially enhances functioning of the PFC.

Adrenergic alpha-2 Receptor Agonists↗

Making your next move: dorsolateral prefrontal cortex and planning a sequence of actions in freely moving monkeys.

Prefrontal damage disrupts planning, as measured by disorders of the activities of daily living (Humphreys & Forde, 1998; Shallice & Burgess, 1991). In a monkey model of this form of planning, a variant of the delayed alternation task was performed by freely moving monkeys. In a 16 x 16-ft. testing room, four feeders were located in the middle of each wall. In the north task, monkeys alternated between feeders: west-north-east-north-west, and so forth. In the south task, the alternation sequence was east-south-west-south-east, and so forth. Neuronal activity was recorded during walking along the eight paths, constituting the north and south tasks. To succeed, monkeys had to memorize the alternation rule and monitor both their place in the sequence and the previously made spatially directed action before deciding to walk to a new location to the left or right of the current location. Responsive dorsolateral prefrontal neurons are strikingly selective. Sustained neuronal activity reflects the spatial direction of an ongoing or upcoming response. It is important that such selective responses occur in one but not both tasks, even though the movements are exactly the same in both tasks and at each location. We suggest that selective neuronal activity is tuned through learning and reflects the fundamental units of a planning mechanism: Individual neurons encode specific components of a sequence of behavioral actions and their temporal order. Populations of such neurons represent all the steps necessary to perform the north and south tasks. The sustained activity of these neurons suggests that planning and working memory mechanisms are integrated.

Animals↗

Intrinsic circuit organization of the major layers and sublayers of the dorsolateral prefrontal cortex in the rhesus monkey.

Intrinsic connections are likely to play important roles in cognitive information processing in the prefrontal association cortex. To gain insight into the organization of these circuits, intracortical connections of major laminar and sublaminar divisions were retrogradely labeled in Walker's area 9 and 46 in rhesus monkeys by using cholera toxin (B-subunit) conjugated to colloidal gold. Microinjections placed within particular cortical laminae produced unique patterns of retrograde labeling. Injections in layers II/III yielded labeling which was laterally widespread (2-7 mm) in supragranular layers, and more narrowly focused, i.e., conforming to a column, in layers IV-VI. In contrast, local circuits associated with layers IV and Vb displayed a regular, cylindrical organization, whereas intrinsic connections of layer Va were laterally extensive (3-5 mm) in layers III and Va. Finally, injections in layer VI gave rise to a narrow column of cell labeling traversing all layers, augmented by laterally extensive labeling (approximately 7 mm) in layer VI. The intrinsic connections of the prefrontal cortex were arrayed within mediolaterally elongated stripes which were often distributed asymmetrically in either the medial or lateral direction. In addition, labeled cells within these mediolaterally oriented fields were frequently grouped within discrete clusters or narrow bands. The intrinsic connections identified in this study differ from the local circuits of corresponding layers reported for primary visual cortex; the unique intrinsic wiring diagram of the prefrontal cortex may be related to its specialized cognitive and mnemonic functions.

Animals↗

Local pharmacological manipulation of extracellular dopamine levels in the dorsolateral prefrontal cortex and caudate nucleus in the rhesus monkey: an in vivo microdialysis study.

The prefrontal cortex, caudate nucleus, and their dopaminergic innervations have been implicated in complex information processing. The present study utilized the in vivo microdialysis technique to characterize the extracellular dopamine levels in the prefrontal cortex and the caudate nucleus in the rhesus monkey. Basal levels of dopamine were consistently found in the caudate nucleus, while levels in the prefrontal cortex were less reliably measured. Manipulation of dopamine levels using tetrodotoxin and high potassium demonstrated that dopamine measured was dependent on neuronal firing. Administration of indirect dopamine agonists d-amphetamine and cocaine into the prefrontal cortex and the caudate nucleus increased extracellular dopamine levels 250% and 5000%, respectively. Amphetamine and cocaine had greater effects on dopamine levels in the caudate than in the prefrontal cortex. Cocaine induced increases appeared to be less than that of amphetamine and the actions of cocaine lasted longer than amphetamine. This study demonstrates the feasibility of using in vivo microdialysis in monitoring neurochemicals in different regions of the rhesus monkey brain.

Animals↗