Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication-free individuals with bipolar disorder: an in vivo1H MRS study

Objectives:  While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy (¹H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N -acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr).
Methods:  Thirty-two medication-free BD subjects (33.8 ± 10.2 years) and 32 matched controls (33.8 ± 9.0 years) underwent a short echo-time (TE = 30 ms) ¹H MRS. An 8-cm³ single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo -inositol, and glutamate were obtained, using the water signal as an internal reference.
Results:  BD subjects had lower Cr + PCr [ F _(1,62) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [ F _(1,62) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites.
Conclusions:  These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.     

Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex

Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N = 84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N‐back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed. Across all three tasks, it was found that carriers of the risk allele consistently exhibited increased activation of the left DLPFC. In addition, the risk allele carriers also exhibited increased activation of the right DLPFC and the left cerebellum during the Stroop task and of the left caudate nucleus during the N‐back task. These findings helped to elucidate the role of CAMKK2 in cognitive functions and in the etiology of SCZ. Hum Brain Mapp 37:2398–2406, 2016. © 2016 Wiley Periodicals, Inc .     

Strength of prefrontal activation predicts intensity of suggestion‐induced pain

Suggestion, a powerful factor in everyday social interaction, is most effective during hypnosis. Subjective evaluations and brain‐imaging findings converge to propose that hypnotic suggestion strongly modulates sensory processing. To reveal the brain regions that mediate such a modulation, we analyzed data from a functional‐magnetic‐resonance‐imaging study on hypnotic‐suggestion‐induced pain on 14 suggestible subjects. Activation strengths in the right dorsolateral prefrontal cortex (DLPFC) during initiation of suggestion for pain correlated positively with the subjective intensity of the subsequent suggestion‐induced pain, as well as with the strengths of the maximum pain‐related activation in the in the secondary somatosensory (SII) cortex. Furthermore, activation of the insula and the anterior cingulate cortex predicted the pain‐related SII activation. The right DLPFC, as an area important for executive functions, likely contributes to functional modulation in the modality‐specific target areas of given suggestions. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Resting‐state and task‐based centrality of dorsolateral prefrontal cortex predict resilience to 1 Hz repetitive transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is used to investigate normal brain function in healthy participants and as a treatment for brain disorders. Various subject factors can influence individual response to rTMS, including brain network properties. A previous study by our group showed that “virtually lesioning” the left dorsolateral prefrontal cortex (dlPFC; important for cognitive flexibility) using 1 Hz rTMS reduced performance on a set‐shifting task. We aimed to determine whether this behavioural response was related to topological features of pre‐TMS resting‐state and task‐based functional networks. 1 Hz (inhibitory) rTMS was applied to the left dlPFC in 16 healthy participants, and to the vertex in 17 participants as a control condition. Participants performed a set‐shifting task during fMRI at baseline and directly after a single rTMS session 1–2 weeks later. Functional network topology measures were calculated from resting‐state and task‐based fMRI scans using graph theoretical analysis. The dlPFC‐stimulated group, but not the vertex group, showed reduced setshifting performance after rTMS, associated with lower task‐based betweenness centrality (BC) of the dlPFC at baseline (p = .030) and a smaller reduction in task‐based BC after rTMS (p = .024). Reduced repeat trial accuracy after rTMS was associated with higher baseline resting state node strength of the dlPFC (p = .017). Our results suggest that behavioural response to 1 Hz rTMS to the dlPFC is dependent on baseline functional network features. Individuals with more globally integrated stimulated regions show greater resilience to rTMS effects, while individuals with more locally well‐connected regions show greater vulnerability.     

Atrophy of the left dorsolateral prefrontal cortex is associated with poor performance in verbal fluency in elderly poststroke women

This study aimed to investigate the association between atrophy in the prefrontal cortex with executive function and verbal fluency in elderly male and female patients poststroke. Thirty elderly female patients with non-aphasic ischemic stroke aged ≥ 60 years and 30 age-matched non-aphasic male patients with ischemic stroke were recruited. Automatic magnetic resonance imaging segmentation was used to assess the volume of the whole prefrontal cortex, along with its subdivisions: anterior cingulate cortex, orbitofrontal cortex and dorsolateral prefrontal cortex. The Semantic Verbal Fluency Test was administered at 3 and 15 months poststroke. At 3 months poststroke, left dorsolateral prefrontal cortex volume was significantly correlated with Verbal Fluency Test score in female patients only (partial coefficient = 0.453, P = 0.045), after controlling for age, education, diabetes, neurological deficit, white matter lesions volume, as well as the location and volume of infarcts. At 15 months poststroke, there remained a significant association between the left dorsolateral prefrontal cortex volume and Verbal Fluency Test (partial coefficient = 0.661, P = 0.001) and between the left prefrontal cortex volume and Verbal Fluency Test (partial coefficient = 0.573, P = 0.004) in female patients after the same adjustments. These findings indicate that atrophy of the left dorsolateral prefrontal cortex contributes to the impairment of verbal fluency in elderly female patients with stroke. Sex differences may be present in the neuropsychological mechanisms of verbal fluency impairment in patients with stroke.     

Direct current stimulation of prefrontal cortex modulates error‐induced behavioral adjustments

Commission of errors and conflict between choices might induce behavioral modulations through adjustments in the executive control of behavior and altered patterns of these modulations are detected in neuropsychiatric disorders. We examined the effects of transcranial Direct Current Stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) on error‐ and conflict‐induced behavioral modulations. Two separate cohorts of participants performed two clinically relevant tests of executive control, respectively. In the Wisconsin Card Sorting Test (WCST), the relevant rule for matching items frequently changed and therefore participants had to detect these unannounced changes by trial and error and alter their rule‐based behavior. In the Stop task, participants had to rapidly respond to a directional go‐signal but inhibit their responses when a stop signal appeared after the go‐signal. Each participant received tDCS (sham, cathodal or anodal) in three separate sessions. Errors led to a slower response in the next trial (post‐error slowing) in both tasks. The tDCS significantly modulated the post‐error slowing in both tasks but did not affect the behavioral adjustments induced by the conflict. The modulation of post‐error slowing by tDCS were polarity‐dependent and also trial specific appearing immediately after errors. In the WCST and Stop task, the post‐error slowing may reflect different processes involved in shifting the behavior‐guiding rule and adjustments in inhibitory control of responses, respectively, and we found that the effective tDCS polarity differed between the two tasks. Here, we show that in two separate cognitive tasks direct current stimulation of DLPFC significantly modulated error‐induced behavioral modulations.     

Depletion of MAP2 expression and laminar cytoarchitectonic changes in dorsolateral prefrontal cortex in adult autistic individuals

The neuropathological substrates underlying the characteristic clinical phenotype of autism are unknown. Neuroimaging studies have identified a decrease in task-related activation in the dorsolateral prefrontal cortex in autism. In the current study, we have analysed the dorsolateral prefrontal cortex in two adult individuals with a clinical diagnosis of autism, using Nissl staining and MAP2 immunohistochemistry. There was unchanged density of both neuronal and glial cell pools, although the autistic individuals had ill-defined neocortical cellular layers, substantially depleted MAP2 neuronal expression, and reduced dendrite numbers. Further studies on a larger number of individuals with autism are needed to establish the clinical relevance of the described changes, especially to determine whether the loss of dendritic markers is age associated or disease specific.     

Low-frequency brain stimulation to the left dorsolateral prefrontal cortex increases the negative impact of social exclusion among those high in personal distress

The dorsolateral prefrontal cortex (DLPFC) is thought to play a key role in the cognitive control of emotion and has therefore, unsurprisingly, been implicated in the regulation of physical pain perception. This brain region may also influence the experience of social pain, which has been shown to activate similar neural networks as seen in response to physical pain. Here, we applied sham or active low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC, previously shown to exert bilateral effects in pain perception, in healthy participants. Following stimulation, participants played the “Cyberball Task”; an online ball-tossing game in which the subject participant is included or excluded. Compared to sham, rTMS did not modulate behavioural response to social exclusion. However, within the active rTMS group only, greater trait personal distress was related to enhanced negative outcomes to social exclusion. These results add further support to the notion that the effect of brain stimulation is not homogenous across individuals, and indicates the need to consider baseline individual differences when assessing response to brain stimulation. This seems particularly relevant in social neuroscience investigations, where trait factors may have a meaningful effect.     

Altered gray matter volume and disrupted functional connectivity of dorsolateral prefrontal cortex in men with heroin dependence

Aim

Chronic heroin use can cause various neuropathological characteristics that may compromise brain function. The present study evaluated the alteration of gray matter volume (GMV) and its resting‐state functional connectivity (rsFC) over the dorsolateral prefrontal cortex (DLPFC) among male heroin users.

Methods

Thirty heroin‐dependent men undergoing methadone maintenance therapy and 30 educational‐level‐ and age‐matched male controls were recruited for this study. To assess their GMV and rsFC, the participants were evaluated using spoiled gradient echo and gradient‐recalled echo planar imaging sequences with a 3‐Tesla General Electric MR scanner under resting state.

Results

The heroin‐dependent men showed lower GMV over the right DLPFC in comparison with the controls. Further evaluation of the rsFC of the right DLPFC revealed a marked decrease in interhemispheric DLPFC connectivity among those with heroin dependence under control of head movement and GMV of the right DLPFC.

Conclusion

Although the mechanism remains unclear, the present study shows that chronic heroin use is associated with alteration of morphology as well as rsFC over the right DLPFC. As the DLPFC plays an imperative role in various domains of cognitive function, service providers for heroin users should consider the impacts of possible DLPFC‐related cognitive deficits on treatment effectiveness.

     

Dissociating the role of the caudate nucleus and dorsolateral prefrontal cortex in the monitoring of events within human working memory

There is evidence that the dorsolateral prefrontal cortex is involved in the monitoring of information held in memory whether it is self‐ordered or externally triggered. However, the functional contribution of the caudate nucleus in the monitoring of events has not yet been studied. We have previously proposed that the striatum is involved when a novel self‐initiated action needs to be generated. The present study aimed to test the hypothesis that the caudate nucleus is significantly more required when the monitoring is self‐ordered as opposed to externally triggered. Self‐ordered monitoring refers to keeping track of which items have been selected so far in order to perform the current selection. Externally triggered monitoring refers to keeping track of which items have been selected by an outside source. Thirteen healthy young adults were scanned using functional magnetic resonance imaging while performing a monitoring task with three conditions: self‐ordered, externally triggered and recognition. As predicted, a significant increase of activity was found in the dorsolateral prefrontal cortex bilaterally when the self‐ordered and externally triggered conditions were compared with the recognition condition. Most importantly, significantly increased activity was found in the right caudate nucleus when comparing the self‐ordered with the recognition condition or with the externally triggered condition, but not when comparing the externally triggered with the recognition condition. We suggest that the caudate nucleus is involved in the planning of a self‐initiated novel action, especially when no clear indication is given for the response choice, and that this may be the case across different domains of cognition.     

Stroop performance in bipolar disorder: further evidence for abnormalities in the ventral prefrontal cortex

OBJECTIVES: Bipolar patients are impaired in Stroop task performance, a measure of selective attention. Structural and functional abnormalities in task-associated regions, in particular the prefrontal cortex (PFC), have been reported in this population. We aimed to examine the relationship between functional abnormalities, impaired task performance and the severity of depressive symptoms in bipolar patients. METHODS: Remitted bipolar patients (n = 10; all medicated), either euthymic or with subsyndromal depression, and age-matched control subjects (n = 11) viewed 10 alternating blocks of incongruent Stroop and control stimuli, naming the colour of the ink. Neural response was measured using functional magnetic resonance imaging. We computed between-group differences in neural response and within-group correlations with mood and anxiety. RESULTS: There were no significant between-group differences in task performance. During the Stroop condition, controls demonstrated greater activation of visual and dorsolateral and ventrolateral prefrontal cortical areas; bipolar patients demonstrated relative deactivation within orbital and medial prefrontal cortices. Depression scores showed a trend towards a negative correlation with the magnitude of orbitofrontal cortex deactivation in bipolar patients, whereas state anxiety correlated positively with activation of dorsolateral PFC and precuneus in controls. CONCLUSIONS: Our findings confirm previous reports of decreased ventral prefrontal activity during Stroop task performance in bipolar patients, and suggest a possible negative correlation between this and depression severity in bipolar patients. These findings further highlight the ventromedial PFC as a potential candidate for illness related dysfunction in bipolar disorder.     

The hippocampus,medial prefrontal cortex,and selective memory retrieval: Evidence from a rodent model of the retrieval‐induced forgetting effect

Inhibition is an important component of many cognitive functions, including memory. For example, the retrieval‐induced forgetting (RIF) effect occurs when extra practice with some items from a study list inhibits the retrieval of the nonpracticed items relative to a baseline condition that does not involve extra practice. Although counterintuitive, the RIF phenomenon may be important for resolving interference by inhibiting potentially competing retrieval targets. Neuroimaging studies suggest that the hippocampus and prefrontal cortex are involved in the RIF effect, but controlled lesion studies have not yet been performed. We developed a rodent model of the RIF training procedure and trained control rats and rats with temporary inactivation of the hippocampus or medial prefrontal cortex (mPFC). Rats were trained on a list of odor cues, presented in cups of digging medium with a buried reward, followed by additional practice trials with a subset of the cues. We then tested the rats' memories for the cues and their association with reward by presenting them with unbaited cups containing the test odorants and measuring how long they persisted in digging. Control rats exhibited a robust RIF effect in which memory for the nonpracticed odors was significantly inhibited. Thus, extra practice with some odor cues inhibited memory for the others, relative to a baseline condition that involved an identical amount of training. Inactivation of either the hippocampus or the mPFC blocked the RIF effect. We also constructed a computational model of a representational learning circuit to simulate the RIF effect. We show in this model that “sideband suppression” of similar memory representations can reproduce the RIF effect and that alteration of the suppression parameters and learning rate can reproduce the lesion effects seen in our rats. Our results suggest that the RIF effect is widespread and that inhibitory processes are an important feature of memory function. © 2014 Wiley Periodicals, Inc.     

The medial prefrontal cortex—lateral entorhinal cortex circuit is essential for episodic‐like memory and associative object‐recognition

The prefrontal cortex directly projects to the lateral entorhinal cortex (LEC), an important substrate for engaging item‐associated information and relaying the information to the hippocampus. Here we ask to what extent the communication between the prefrontal cortex and LEC is critically involved in the processing of episodic‐like memory. We applied a disconnection procedure to test whether the interaction between the medial prefrontal cortex (mPFC) and LEC is essential for the expression of recognition memory. It was found that male rats that received unilateral NMDA lesions of the mPFC and LEC in the same hemisphere, exhibited intact episodic‐like (what‐where‐when) and object‐recognition memories. When these lesions were placed in the opposite hemispheres (disconnection), episodic‐like and associative memories for object identity, location and context were impaired. However, the disconnection did not impair the components of episodic memory, namely memory for novel object (what), object place (where) and temporal order (when), per se. Thus, the present findings suggest that the mPFC and LEC are a critical part of a neural circuit that underlies episodic‐like and associative object‐recognition memory. © 2015 Wiley Periodicals, Inc.     

The effect of meditation on brain structure: cortical thickness mapping and diffusion tensor imaging

A convergent line of neuroscientific evidence suggests that meditation alters the functional and structural plasticity of distributed neural processes underlying attention and emotion. The purpose of this study was to examine the brain structural differences between a well-matched sample of long-term meditators and controls. We employed whole-brain cortical thickness analysis based on magnetic resonance imaging, and diffusion tensor imaging to quantify white matter integrity in the brains of 46 experienced meditators compared with 46 matched meditation-naïve volunteers. Meditators, compared with controls, showed significantly greater cortical thickness in the anterior regions of the brain, located in frontal and temporal areas, including the medial prefrontal cortex, superior frontal cortex, temporal pole and the middle and interior temporal cortices. Significantly thinner cortical thickness was found in the posterior regions of the brain, located in the parietal and occipital areas, including the postcentral cortex, inferior parietal cortex, middle occipital cortex and posterior cingulate cortex. Moreover, in the region adjacent to the medial prefrontal cortex, both higher fractional anisotropy values and greater cortical thickness were observed. Our findings suggest that long-term meditators have structural differences in both gray and white matter.     

The role of ventral medial prefrontal cortex in social decisions: Converging evidence from fMRI and frontotemporal lobar degeneration

The ventral medial prefrontal cortex (vmPFC) has been implicated in social and affectively influenced decision-making. Disease in this region may have clinical consequences for social judgments in patients with frontotemporal lobar degeneration (FTLD). To test this hypothesis, regional cortical activation was monitored with fMRI while healthy adults judged the acceptability of brief social scenarios such as cutting into a movie ticket line or going through a red light at 2 AM. The scenarios described: (i) a socially neutral condition, (ii) a variant of each scenario containing a negatively valenced feature, and (iii) a variant containing a positively valenced feature. Results revealed that healthy adults activated vmPFC during judgments of negatively valenced scenarios relative to positive scenarios and neutral scenarios. In a comparative behavioral study, the same social decision-making paradigm was administered to patients with a social disorder due to FTLD. Patients differed significantly from healthy controls, specifically showing less sensitivity to negatively valenced features. Comparative anatomical analysis revealed considerable overlap of vmPFC activation in healthy adults and vmPFC cortical atrophy in FTLD patients. These converging results support the role of vmPFC in social decision-making where potentially negative consequences must be considered.     

Medial prefrontal cortex N‐methyl‐D‐aspartate receptor/nitric oxide/cyclic guanosine monophosphate pathway modulates both tachycardic and bradycardic baroreflex responses

Neural reflex mechanisms, such as the baroreflex, are involved in regulating cardiovascular system activity. Previous results showed that the ventral portion of the medial prefrontal cortex (vMPFC) is involved in modulation only of the cardiac baroreflex bradycardic component. Moreover, vMPFC N‐methyl‐D‐aspartate (NMDA) receptors modulate the bradycardia baroreflex, but the baroreflex tachycardic component has not been investigated. Furthermore, glutamatergic neurotransmission into the vMPFC is involved in activation of the cardiac sympathetic and parasympathetic nervous system. Finally, it has been demonstrated that glutamatergic neurotransmission into the vMPFC can be modulated by the endocannabinoid system and that activation of the CB1 cannabinoid receptor by anandamide, an endocannabinoid, can decrease both cardiac baroreflex bradycardic and tachycardic responses. Thus, there is the possibility that glutamatergic neurotransmission into the vMPFC does not modulate only the cardiac bradycardic component of the baroreflex. Therefore, the present study investigated whether glutamatergic neurotransmission into the vMPFC modulates both cardiac baroreflex bradycardic and tachycardic responses. We found that vMPFC bilateral microinjection of the NMDA receptor antagonist AP7 (4 nmol/200 nl), of a selective inhibitor of neuronal nitric oxide (NO) synthase N‐propyl (0.08 nmol/200 nl), of the NO scavenger carboxy‐PTIO (2 nmol/200 nl), or of the NO‐sensitive guanylate cyclase ODQ (2 nmol/200 nl) decreased the baroreflex activity in unanesthetized rats. Therefore, our results demonstrate the participation of NMDA receptors, production of NO, and activation of guanylate cyclase in the vMPFC in the modulation of both cardiac baroreflex bradycardic and tachycardic responses. © 2013 Wiley Periodicals, Inc.