1H magnetic resonance spectroscopy investigation of the dorsolateral prefrontal cortex in bipolar disorder patients

BACKGROUND: Magnetic resonance spectroscopy studies (MRS) reported abnormally low levels of N-acetylaspartate (NAA, a marker of neuronal integrity) in dorsolateral prefrontal cortex (DLPFC) of adult bipolar patients, suggesting possible neuronal dysfunction. Furthermore, recent MRS reports suggested possible lithium-induced increase in NAA levels in bipolar patients. We examined with in vivo (1)H MRS NAA levels in the DLPFC of adult bipolar patients. METHODS: Ten DSM-IV bipolar disorder patients (6 lithium-treated, 4 drug-free) and 32 healthy controls underwent a short echo-time 1H MRS session, which localized an 8 cm3 single-voxel in the left DLPFC using a STEAM sequence. RESULTS: No significant differences between the two groups were found for NAA, choline-containing molecules (GPC+PC), or phosphocreatine plus creatine (PCr+Cr) (Student t-test, p > 0.05). Nonetheless, NAA/PCr+Cr ratios were significantly increased in lithium-treated bipolar subjects compared to unmedicated patients and healthy controls (Mann-Whitney U-test, p < 0.05). LIMITATIONS: Relatively small sample size may have reduced the statistical power of our analyses and the utilization of a single-voxel approach did not allow for the examination of other cortical brain areas. CONCLUSIONS: This study did not find abnormally reduced levels of NAA in left DLPFC of adult bipolar patients, in a sample of patients who were mostly on medications. However, elevated NAA/PCr+Cr ratios were shown in lithium-treated bipolar patients. Longitudinal 1H MRS studies should further examine NAA levels in prefrontal cortex regions in untreated bipolar patients before and after mood stabilizing treatment.     

The influence of rTMS over the left dorsolateral prefrontal cortex on Stroop task performance

Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) can improve cognitive processing. Neuroimaging studies have shown the engagement of the left dorsolateral prefrontal cortex (DLPFC) in executive functioning, and more specifically during selective attention. In the present study, the influence of high-frequency rTMS over the left DLPFC on Stroop task performance in healthy female volunteers was investigated. As expected, reaction time on both the incongruent and congruent trials decreased significantly after stimulation, and there was no difference with regard to the Stroop interference effect. Mood remained unchanged after rTMS. Such a pattern is consistent with the role of the left DLPFC in implementing top–down attentional control.     

Repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex improves probabilistic category learning

Traditionally, it has been thought that probabilistic category learning, one of the implicit memory functions, is dependent on the basal ganglia. However, there is growing evidence indicating the involvement of the dorsolateral prefrontal cortex (DLPFC) in probabilistic category learning. In order to identify the causal role of DLPFC in probabilistic category learning, we investigated whether repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC influences the learning ability in healthy subjects using the weather prediction task (WPT). Application of 10?Hz rTMS over the left DLPFC induced significant improvement in the total hit rate during the total trials of the WPT, compared with sham stimulation. Specifically, the improvement was significant in the early and late learning blocks of the WPT, but not in the intermediate block of learning. These results indicate that the left DLPFC may play an important role in probabilistic category learning, possibly by influencing not only on embodied information application in late stage of the learning but also on memory encoding for working memory demands in early stage of the learning via frontostriatal and frontohippocampal circuits, respectively. They also may lend support to the possibility that rTMS can improve implicit learning ability in patients with basal ganglia disorders.     

Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression

BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) is involved in the pathophysiology of major depression. In particular, metabolic (functional hypometabolism) and structural alterations have been described. In this study metabolic changes within the DLPFC of severely depressed patients before and after electroconvulsive therapy (ECT) were evaluated by proton STEAM spectroscopy (1H-MRS). METHOD: Twelve severely depressed patients with a diagnosis of major depressive episode, unipolar with melancholic features (DSM-IV), were enrolled, and the left dorsolateral prefrontal cortex (DLPFC) was investigated before and after unilateral ECT by 1H-MRS. Three of the four non-responding patients were remeasured a third time after a combined ECT/antidepressant pharmacotherapy. The results were compared with 12 age- and gender-matched controls. RESULTS: In depressed patients reduced glutamate/glutamine (Glx) levels were measured pre-ECT; Glx concentrations correlated negatively with severity of depression. After successful treatment, Glx increased significantly and levels no longer differed from those of age-matched controls. CONCLUSIONS: Our results indicate that major depressive disorder is accompanied by state-dependent metabolic alterations, especially in glutamate/glutamine metabolism, which can be reversed by successful ECT.     

Connections of the dorsolateral prefrontal cortex with the thalamus: a probabilistic tractography study

Purpose

The dorsolateral prefrontal cortex (DLPFC) is a cortical area involved in higher cognitive functions, and at the center of the pathophysiology of mental disorders such as depression and schizophrenia. Considering these major roles and the development of deep brain stimulation, the object of this study was to assess the patterns of connectivity of the DLPFC with its main subcortical relay, the thalamus, with the help of probabilistic tractography.

Methods

We used T1-weighted imaging and diffusion data from 18 subjects from the Human Connectome Project. The DLPFC and the thalamic nuclear groups were defined using the combination of atlases, sulcogyral anatomy and cytoarchitectonic data. Probabilistic tractography was performed from the DLPFC to the thalamus. The patterns of connectivity were assessed using two indexes: (1) a connectivity index (CI) which evaluate the strength of connection (2) an asymmetry index (AI) which explores the inter-hemispheric variability.

Results

The analysis of CI showed significant connections between the DLPFC and the dorsomedial nuclei (p < 0.05), the anterior nuclear groups (p < 0.05) and the right centromedian nucleus (p < 0.05). No link was found between handedness and AI (p > 0.05). Most of subjects (15/18) had a right predominance of the thalamo cortical connections of the DLPFC.

Conclusions

Probabilistic tractography appears as a valuable non-invasive tool for the exploration of the thalamocortical connections between the dorsolateral prefrontal cortex and thalamic nuclei. It allowed to show different inter-hemispheric patterns of connectivity, and highlighted the centromedian nucleus as a key subcortical relay of executive functions.

     

Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex

1. An oculomotor delayed-response task was used to examine the spatial memory functions of neurons in primate prefrontal cortex. Monkeys were trained to fixate a central spot during a brief presentation (0.5 s) of a peripheral cue and throughout a subsequent delay period (1-6 s), and then, upon the extinction of the fixation target, to make a saccadic eye movement to where the cue had been presented. Cues were usually presented in one of eight different locations separated by 45 degrees. This task thus requires monkeys to direct their gaze to the location of a remembered visual cue, controls the retinal coordinates of the visual cues, controls the monkey's oculomotor behavior during the delay period, and also allows precise measurement of the timing and direction of the relevant behavioral responses. 2. Recordings were obtained from 288 neurons in the prefrontal cortex within and surrounding the principal sulcus (PS) while monkeys performed this task. An additional 31 neurons in the frontal eye fields (FEF) region within and near the anterior bank of the arcuate sulcus were also studied. 3. Of the 288 PS neurons, 170 exhibited task-related activity during at least one phase of this task and, of these, 87 showed significant excitation or inhibition of activity during the delay period relative to activity during the intertrial interval. 4. Delay period activity was classified as directional for 79% of these 87 neurons in that significant responses only occurred following cues located over a certain range of visual field directions and were weak or absent for other cue directions. The remaining 21% were omnidirectional, i.e., showed comparable delay period activity for all visual field locations tested. Directional preferences, or lack thereof, were maintained across different delay intervals (1-6 s). 5. For 50 of the 87 PS neurons, activity during the delay period was significantly elevated above the neuron's spontaneous rate for at least one cue location; for the remaining 37 neurons only inhibitory delay period activity was seen. Nearly all (92%) neurons with excitatory delay period activity were directional and few (8%) were omnidirectional. Most (62%) neurons with purely inhibitory delay period activity were directional, but a substantial minority (38%) was omnidirectional. 6. Fifteen of the neurons with excitatory directional delay period activity also had significant inhibitory delay period activity for other cue directions. These inhibitory responses were usually strongest for, or centered about, cue directions roughly opposite those optimal for excitatory responses.(ABSTRACT TRUNCATED AT 400 WORDS)     

Segregation of working memory functions within the dorsolateral prefrontal cortex

It is now widely accepted that the prefrontal cortex (PFC) plays a critical role in the neural network subserving working memory (WM). At least three related questions are still under debate: (1) is the PFC critical for all constituent processes of WM (i.e., short-term storage, manipulation, and utilization of mental representations) or only in one or a few of them? (2) Is there segregation of function among different cytoarchitectonic subdivisions of the PFC? (3) If this be the case, is this segregation based on the nature of the information being processed or on the type of cognitive operation performed? The present review article describes findings in the monkey supporting a modular "domain-specific" model of PFC functional organization with respect to WM operations. In this model, the dorsolateral prefrontal cortex (DLPFC) is composed of several subregions, based primarily on the nature of the information being processed in WM. Storage and processing functions are integrally related in each area. Future studies designed to map as yet uncharted areas of prefrontal cortex with refined anatomical and physiological approaches may provide a critical test of the model and evaluate the extent to which it applies generally or, instead, mainly to visual domains or only to dorsolateral convexity areas.     

The role of the dorsolateral prefrontal cortex in implicit procedural learning

We studied the role of the dorsolateral prefrontal cortex in procedural learning. Normal subjects completed several blocks of a serial reaction time task using only one hand without or with concurrent non-invasive repetitive transcranial magnetic stimulation. To disrupt their function transiently, stimulation was applied at low intensity over the supplementary motor area or over the dorsolateral prefrontal cortex contralateral or ipsilateral to the hand used for the test. Stimulation to the contralateral dorsolateral prefrontal cortex markedly impaired procedural implicit learning, as documented by the lack of significant change in response times during the task. Stimulation over the other areas did not interfere with learning. These results support the notion of a critical role of contralateral dorsolateral prefrontal structures in learning of motor sequences.     

Microstimulation of monkey dorsolateral prefrontal cortex impairs antisaccade performance

The dorsolateral prefrontal cortex (DLPFC) has been implicated in various cognitive functions, including response suppression. This function is frequently probed with the antisaccade task, which requires suppression of the automatic tendency to look toward a flashed peripheral stimulus (prosaccade), and instead generate a voluntary saccade to the mirror location. To test whether activity in the DLPFC is causally linked to antisaccade performance, we applied electrical microstimulation to sites in the DLPFC of two monkeys, while they performed randomly interleaved pro- and antisaccade trials. Microstimulation resulted in significantly longer saccadic reaction times for ipsilaterally directed prosaccades and antisaccades, and increased the error rate on ipsilateral antisaccade trials. These findings provide causal evidence that activity in the DLPFC influences saccadic eye movements.     

Go-no-go task performance improvement after anodal transcranial DC stimulation of the left dorsolateral prefrontal cortex in major depression

BACKGROUND: We recently showed that repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) can affect the performance in an affective go-no-go (AGN) task. We aimed to extend this previous investigation testing whether one session of anodal transcranial direct current stimulation (tDCS) of the left DLPFC, as compared with anodal occipital and sham tDCS, affects this AGN task performance. METHODS: Twenty-six patients with major depression were randomized to receive anodal tDCS of the left DLPFC, occipital cortex or sham tDCS (the cathode electrode was placed over the frontopolar area for the three conditions). An AGN task was performed immediately before and after treatment. Performance changes (pre and post-treatment) were compared across groups of treatment and correlated with Hamilton Depression Rating Scale (HDRS) score changes. RESULTS: The results show that anodal stimulation of the left DLPFC was the only condition that induced a significant improvement in task performance as shown by the increase in the number of correct responses. In addition, this effect was specific for figures with positive emotional content. This performance enhancement was not correlated with mood changes after 10 days of tDCS treatment. LIMITATIONS: Although the effects of tDCS are less focal than rTMS, it can induce a longer and stronger modulation of cortical excitability. CONCLUSIONS: Our findings suggest that left DLPFC activity is associated with positive emotional processing, confirming and extending results of previous studies that associated right DLPFC and orbito-frontal cortex activity with emotional processing. Furthermore the effects of tDCS on mood and cognition seem to be independent in major depression. These lines of evidence together shed light on the neural circuitry involved with emotional processing in major depression.     

Altered MHC class I expression in dorsolateral prefrontal cortex of nonsmoker patients with schizophrenia

Schizophrenia (SZ) is a psychiatric disease with plausible neurodevelopmental etiology. Although genetic studies show significant association of immune molecules loci such as major histocompatibility complex (MHC) class I with SZ, it is not clear whether these immune molecules are involved in the pathology observed in SZ brains. MHC class I and the classical pathway components of complement system (C1q and C3) have been shown to regulate brain neuronal maturation and function. We have examined the expression of MHC class I and complement protein C3 in two frontal cortical regions of postmortem brains of SZ patients. Since cigarette smoking may modulate MHC class I protein expression and a higher rate of smoking is observed in SZ patients, we studied the expression of MHC class I and C3 in relation to the presence of smoking. We found that MHC class I protein expression is reduced in the dorsolateral prefrontal cortex (DLPFC) but not in the orbitofrontal cortex (OFC) of nonsmoker SZ patients. We did not observe SZ-associated changes in C3 mRNA expression. Our exploratory research suggests a potential involvement of MHC class I in SZ and implies that smoking might modulate its expression.     

Involvement of the dorsolateral prefrontal cortex of monkeys in visuospatial target selection

To examine the involvement of the dorsolateral prefrontal cortex (PFC) in visuospatial target selection, we induced local, reversible inactivation with muscimol at various sites in the dorsolateral PFC of two rhesus monkeys while they performed oculomotor visual search (OVS) and oculomotor detection (OD) tasks. The OVS task required the subject to select a target stimulus from among distractors and to make a saccade to the target location (target selection was required for correct performance), whereas the OD task only required a saccade to the target (target selection was not required for correct performance). The local injection of muscimol (5 microg, 1 microl) into the dorsolateral PFC induced a specific deficit in the OVS task but not in the OD task. The deficit in the OVS task was characterized by the disordering of saccades for some (mostly a few) particular target locations as well as by prolongation of the time required for the visual search in most cases. The target locations affected by muscimol were biased to the contralateral visual field. Further, the OVS task with "pop-out" and "non-pop-out" conditions was similarly impaired by muscimol injection. These results suggest that the dorsolateral PFC plays a role in target selection in visual space to guide goal-directed motor acts and particular sites are involved in target selection for a particular visuospatial coordinate. Further, this function of the dorsolateral PFC appears to involve both top-down (active) and bottom-up (passive) target-selection/selective attention processes to control interfering information (distractors).     

Neural correlates of a decision in the dorsolateral prefrontal cortex of the macaque

To make a visual discrimination, the brain must extract relevant information from the retina, represent appropriate variables in the visual cortex and read out this representation to decide which of two or more alternatives is more likely. We recorded from neurons in the dorsolateral prefrontal cortex (areas 8 and 46) of the rhesus monkey while it performed a motion discrimination task. The monkey indicated its judgment of direction by making appropriate eye movements. As the monkey viewed the motion stimulus, the neural response predicted the monkey's subsequent gaze shift, hence its judgment of direction. The response comprised a mixture of high-level oculomotor signals and weaker visual sensory signals that reflected the strength and direction of motion. This combination of sensory integration and motor planning could reflect the conversion of visual motion information into a categorical decision about direction and thus give insight into the neural computations behind a simple cognitive act.     

The role of the dorsolateral prefrontal cortex in the inhibition of stereotyped responses

Stereotyped behaviors should be inhibited under some circumstances in order to encourage appropriate behavior. Psychiatrists have used the modified rock-paper-scissors (RPS) task to examine the inhibition of stereotyped behavior. When subjects are required to lose in response to a gesture, it is difficult for them to lose, and they have a tendency to win involuntarily. It is thought that the win response is the stereotyped response in the RPS task, and the difficulty in making positive attempts to lose is due to the requirement for inhibition of the stereotyped response. In this study, we investigated the brain regions related to inhibition of the stereotyped response using functional magnetic resonance imaging (fMRI). Subjects were assigned to one of two groups: the “win group” or the “lose group.” The lose group showed higher activation of the left dorsolateral prefrontal cortex (DLFPC) when compared to the win group. We also delivered transcranial magnetic stimulation (TMS) while the subjects performed the modified RPS task to investigate whether the left DLPFC (middle frontal gyrus, Brodmann area, BA 9) was directly involved in the inhibition of the stereotyped response. When TMS was delivered before onset of the visual stimulus, the subjects displayed increased response errors. In particular, the subjects had a tendency to win erroneously in a lose condition even though they were required to lose. These results indicate involvement of the left DLPFC in inhibition of the stereotyped responses, which suggests that this region is associated with inhibition of the preparatory setting for stereotyped responses rather than inhibition of ongoing processing to produce a stereotyped response.     

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.     

Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients

Alterations in the structure and physiology of the prefrontal cortex (PFC) have been found in different psychiatric disorders and some of them involve inhibitory networks, especially in schizophrenia and major depression. Changes in the structure of these networks may be mediated by the polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, expressed in the PFC exclusively by interneurons. Different studies have found that PSA-NCAM expression in the hippocampus and the amygdala is altered in schizophrenia, major depression and animal models of these disorders, in parallel to changes in the expression of molecules related to inhibitory neurotransmission and synaptic plasticity. We have analyzed post-mortem sections of the dorsolateral PFC from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients, to check whether similar alterations occur. PSA-NCAM was found in neuronal somata and neuropil puncta, many of which corresponded to interneurons. PSA-NCAM expression was only reduced significantly in schizophrenic patients, in parallel to a decrease in glutamic acid-decarboxylase-67 (GAD67) and to an increased expression of vesicular glutamate transporter 1 (VGLUT1) in the white matter. Depressed patients showed significant decreases in synaptophysin (SYN) and VGLUT1 expression. Whereas in bipolar patients, decreases in VGLUT1 expression have also been found, together with a reduction of GAD67. These results indicate that the expression of synaptic proteins is altered in the PFC of patients suffering from these disorders and that, particularly in schizophrenia, abnormal PSA-NCAM and GAD67 expression may underlie the alterations observed in inhibitory neurotransmission.     

Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI

The known regional abnormality of the dorsolateral prefrontal cortex (DLPFC) and its role in various neural circuits in schizophrenia has given prominence to its importance in studies on the dysconnection associated with schizophrenia. Abnormal functional connectivities of the DLPFC have been found during various goal-directed tasks; however, the occurrence of the abnormality during rest in patients with schizophrenia has rarely been reported. In the present study, we selected bilateral Brodmann's area 46 as region of interest and analyzed the differences in the DLPFC functional connectivity pattern between 17 patients with first-episode schizophrenia (FES) and 17 matched controls using resting-state fMRI. We found that the bilateral DLPFC showed reduced functional connectivities to the parietal lobe, posterior cingulate cortex, thalamus and striatum in FES patients. We also found enhanced functional connectivity between the left DLPFC and the left mid-posterior temporal lobe and the paralimbic regions in FES patients. Our results suggest that functional dysconnectivity associated with the DLPFC exists in schizophrenia during rest. This may be partially related to disturbance in the intrinsic brain activity.     

Enhancement of pain inhibition by working memory with anodal transcranial direct current stimulation of the left dorsolateral prefrontal cortex

The aim of this study was to examine whether transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) enhances pain inhibition by improving working memory (WM). Forty healthy volunteers participated in two tDCS sessions. Pain was evoked by electrical stimulation at the ankle. Participants performed an n-back task (0-back and 2-back). The experimental protocol comprised five counterbalanced conditions (0-back, 2-back, pain, 0-back with pain and 2-back with pain) that were performed twice (pre-tDCS baseline and during tDCS). Compared with the pre-tDCS baseline values, anodal tDCS decreased response times for the 2-back condition (p < 0.01) but not for the 0-back condition (p > 0.5). Anodal tDCS also decreased pain ratings marginally in the 2-back with pain condition, but not the 0-back with pain condition (p = 0.052 and p > 0.2, respectively). No effect was produced by sham tDCS for any condition (p > 0.2). These results indicate that tDCS of the left DLPFC may enhance pain inhibition by improving WM.