Dorsal Prefrontal Cortex Research Articles

A cross-cultural comparison of intrinsic and extrinsic motivational drives for learning.

Intrinsic motivational drives, like the autonomous feeling of control, and extrinsic motivational drives, like monetary reward, can benefit learning. Extensive research has focused on neurobiological and psychological factors that affect these drives, but our understanding of the sociocultural factors is limited. Here, we compared the effects of autonomy and rewards on episodic recognition memory between students from Dutch and Chinese universities. In an exploratory learning task, participants viewed partially obscured objects that they needed to subsequently remember. We independently manipulated autonomy, as volitional control over an exploration trajectory, as well as the chance to receive monetary rewards. The learning task was followed by memory tests for objects and locations. For both cultural groups, we found that participants learned better in autonomous than non-autonomous conditions. However, the beneficial effect of reward on memory performance was stronger for Chinese than for Dutch participants. By incorporating the sociocultural brain perspective, we discuss how differences in norms and values between Eastern and Western cultures can be integrated with the neurocognitive framework about dorsal lateral and ventral medial prefrontal cortex and dopaminergic reward modulations on learning and memory. These findings have important implications for understanding the neurocognitive mechanisms in which both autonomy and extrinsic rewards are commonly used to motivate students in the realm of education and urge more attention to investigate cultural differences in learning.

Brain activity associated with emotion regulation predicts individual differences in working memory ability.

Previous behavioral research has found that working memory is associated with emotion regulation efficacy. However, there has been mixed evidence as to whether the neural mechanisms between emotion regulation and working memory overlap. The present study tested the prediction that individual differences on the working memory subtest of the Weschler Adult Intelligence Scale (WAIS-IV) could be predicted from the pattern of brain activity produced during emotion regulation in regions typically associated with working memory, such as the dorsal lateral prefrontal cortex (dlPFC). A total of 101 participants completed an emotion regulation fMRI task in which they either viewed or reappraised negative images. Participants also completed working memory test outside the scanner. A whole brain covariate analysis contrasting the reappraise negative and view negative BOLD response found that activity in the right dlPFC positively related to working memory ability. Moreover, a multivoxel pattern analysis approach using tenfold cross-validated support vector regression in regions-of-interest associated with working memory, including bilateral dlPFC, demonstrated that we could predict individual differences in working memory ability from the pattern of activity associated with emotion regulation. These findings support the idea that emotion regulation shares underlying cognitive processes and neural mechanisms with working memory, particularly in the dlPFC.

Modulation effects of repetitive transcranial magnetic stimulation on target and indirect target nodes in patients with major depressive disorder

Clinical studies intensively highlight two critical brain regions, i,e, dorsal lateral prefrontal cortex (DLPFC) (target node) and subgenual anterior cingulate cortex (sgACC) (indirect target node) for the treatment of neuroimaging-guided repetitive transcranial magnetic stimulation (rTMS) in major depressive disorder (MDD). However, it remains unclear whether the clinical rTMS treatment could modulate the activity of the target and indirect target nodes in MDD patients. We aim to identify the rTMS-induced alteration of brain local and functional connectivity (FC) activities in the target and indirect target nodes. 38 patients with MDD were recruited for taking part in the 2-week rTMS treatment. We identified left DLPFC and right sgACC as the target and indirect target nodes for each participant, using the neuroimaging guided method, and further explored the rTMS-induced modulation on the brain functional activity of the two nodes. Ultimately, 28 patients were included in the analysis. We found that subjects had significant improvement in depressive symptoms, and their brain functional activities were reorganized. rTMS reduced the FC activity between the target and indirect target nodes, while the brain local activity in these nodes did not show rTMS-induced changes. The FC reduction was not associated with improvement in depressive symptoms. These results confirmed the clinical significance of the target node (DLPFC) and indirect target node (sgACC) in the rTMS treatment of MDD, and further shed light on the brain functional reorganization underpinning clinical practice of rTMS.

Personalised transcranial magnetic stimulation for treatment-resistant depression, depression with comorbid anxiety and negative symptoms of schizophrenia: a narrative review.

Transcranial magnetic stimulation (TMS) is a promising intervention for treatment-resistant psychiatric disorders. However, conventional TMS typically utilises a one-size-fits-all approach when determining stimulation targets. Recent retrospective brain circuit-based analyses using lesion network mapping have suggested that a left dorsal lateral prefrontal cortex target has a higher efficacy for alleviating depression symptoms, a dorsomedial prefrontal cortex target is more effective for anxiety symptoms, and a rostromedial prefrontal cortex target is effective for schizophrenia-associated psychiatric symptoms. Nonetheless, symptom-specific brain circuit targeting has not been tested prospectively. We conducted a narrative review of selected literature to investigate individualised targeting for TMS and discuss potential future directions to elucidate the efficacy of this approach.

Meta-Analysis Reveals That Explore-Exploit Decisions are Dissociable by Activation in the Dorsal Lateral Prefrontal Cortex, Anterior Insula, and the Anterior Cingulate Cortex.

Explore-exploit research faces challenges in generalizability due to a limited theoretical basis for exploration and exploitation. Neuroimaging can help identify whether explore-exploit decisions involve an opponent processing system to address this issue. Thus, we conducted a coordinate-based meta-analysis (N=23 studies) finding activation in the dorsal lateral prefrontal cortex, anterior insula, and anterior cingulate cortex during exploration versus exploitation, which provides some evidence for opponent processing. However, the conjunction of explore-exploit decisions was associated with activation in the dorsal anterior cingulate cortex and dorsal medial prefrontal cortex, suggesting that these brain regions do not engage in opponent processing. Furthermore, exploratory analyses revealed heterogeneity in brain responses between task types during exploration and exploitation respectively. Coupled with results suggesting that activation during exploration and exploitation decisions is generally more similar than it is different suggests, there remain significant challenges in characterizing explore-exploit decision making. Nonetheless, dlPFC, AI, and ACC activation differentiate explore and exploit decisions and identifying these responses can aid in targeted interventions aimed at manipulating these decisions.

Effects of DLPFC tDCS Followed by Treadmill Training on Dual-Task Gait and Cortical Excitability in Parkinson’s Disease: A Randomized Controlled Trial

Background Gait disturbances are exacerbated in people with Parkinson’s disease (PD) during dual-task walking (DTW). Transcranial direct current stimulation (tDCS) has been shown to exert beneficial effects on gait performance and cortical excitability in PD; however, its combined effects with treadmill training (TT) remain undetermined. Objective To investigate the effects of tDCS followed by TT on DTW performance and cortical excitability in individuals with PD. Methods Thirty-four PD participants were randomized to dorsal lateral prefrontal cortex (DLPFC) tDCS and TT group (DLPFC tDCS + TT group) or sham tDCS and TT group (sham tDCS + TT group) for 50 minutes per session (20 minutes tDCS followed by 30 minutes TT), 12 sessions within 5 weeks (2-3 sessions each week). Outcome measures included cognitive dual-task walking (CDTW), motor dual-task walking (MDTW), usual walking performance, cortical excitability, functional mobility, cognitive function, and quality of life. Results The DLPFC tDCS + TT group exerted significantly greater improvement in CDTW velocity (P = .046), cadence (P = .043), and stride time (P = .041) compared to sham tDCS + TT group. In addition, DLPFC tDCS + TT group demonstrated a significant increase in resting motor threshold of stimulated hemisphere compared with sham tDCS + TT group (P = .026). However, no significant differences between groups were found in MDTW performance and other outcomes. Conclusion Twelve-session DLPFC tDCS followed by TT significantly improved CDTW performance and decreased cortical excitability more than TT alone in individuals with PD. Applying DLPFC tDCS prior to TT could be suggested for gait rehabilitation in individuals with PD. Clinical trial registration number: Australian New Zealand Clinical Trials Registry ACTRN12622000101785

The characteristics of WM in individuals with depressive tendencies: A functional near-infrared spectroscopy (fNIRS) study

Individuals with depressive tendencies are considered to be at high risk for the onset of depressive disorders. Currently, most research focuses on the impairment of working memory in patients with depression, while there is less attention paid to the WM of individuals with depressive tendencies, and their neural mechanisms underlying it are poorly understood. Therefore, this study focuses on the characteristics and neural mechanisms of WM in individuals with depressive tendencies. This study uses functional near-infrared spectroscopy (fNIRS) to monitor the concentration of Oxy-Hb in the prefrontal cortex and employs the n-back paradigm, designing three levels of load: 0, 1, and 2, to examine the characteristics of WM and its neural mechanisms in individuals with depressive tendencies. Behavioral results show that the accuracy rates of individuals with depressive tendencies is significantly lower than that of healthy individuals, and under the 0-back condition, the reaction time of individuals with depressive tendencies is significantly higher than that of healthy control individuals. Near-infrared results indicate that the activation level in the frontal pole and the dorsal lateral prefrontal cortex of individuals with depressive tendencies is significantly lower than that of healthy control individuals. The β values of channels 2, 7, and 9 are significantly negatively correlated with the Beck Depression Inventory scores of the participants. The results suggest that the reduced activation of the frontal pole and dorsal lateral prefrontal cortex in individuals with depressive tendencies leads to poorer WM performance compared to healthy control individuals. This is a rare brain evidence of the characteristics of WM in individuals with depressive tendencies, which can provide a deeper understanding of the WM characteristics of individuals with depressive tendencies.

Abnormal structure and function of white matter in obsessive-compulsive disorder

BackgroundAbnormal structure and function of gray matter (GM) have been discovered in the cortico-striatal-thalamic-cortical (CSTC) circuit in obsessive-compulsive disorder (OCD). The GM structure and function may be influenced by the structure and function of the white matter (WM). Therefore, it is crucial to explore the characteristics of WM in OCD. MethodsDiffusion tensor imaging and resting-state functional magnetic resonance imaging data of 52 patients with OCD and 39 healthy controls (HCs) were collected. The tract-based spatial statistics, amplitude of low-frequency fluctuations (ALFF), and structural-functional coupling approaches were utilized to explore the WM structure and function. Furthermore, the relationship between the abnormal WM structure and function and clinical symptoms of OCD was investigated using Pearson's correlation. Support vector machine was performed to evaluate whether patients with OCD could be identified with the changed WM structure and function. ResultsCompared to HCs, the lower fractional anisotropy (FA) values of four clusters including the superior corona radiata, anterior corona radiata, right superior longitudinal fasciculus, corpus callosum, left posterior corona radiata, fornix, and the right anterior limb of internal capsule, reduced ALFF/FA ratio in the left anterior thalamic radiation (ATR), and the decreased functional connectivity between the left ATR and the left dorsal lateral prefrontal cortex within CSTC circuit at rest were observed in OCD. The decreased ALFF/FA ratio in the left ATR negatively correlated with Yale-Brown Obsessive-Compulsive Scale obsessive thinking scores and Hamilton Anxiety Rating Scale scores in OCD. Furthermore, the features that combined the abnormal WM structure and function performed best in distinguishing OCD from HCs with the appropriate accuracy (0.80), sensitivity (0.82), as well as specificity (0.80). ConclusionCurrent research discovered changed WM structure and function in OCD. Furthermore, abnormal WM structural-functional coupling may lead to aberrant GM connectivity within the CSTC circuit at rest in OCD.Trial Registration: Study on the mechanism of brain network in obsessive-compulsive disorder with multi-model magnetic resonance imaging (ChiCTR-COC-17013301).

Sex differences in aberrant functional connectivity of three core networks and subcortical networks in medication-free adolescent-onset major depressive disorder.

Major depressive disorder demonstrated sex differences in prevalence and symptoms, which were more pronounced during adolescence. Yet, research on sex-specific brain network characteristics in adolescent-onset major depressive disorder remains limited. This study investigated sex-specific and nonspecific alterations in resting-state functional connectivity of three core networks (frontoparietal network, salience network, and default mode network) and subcortical networks in adolescent-onset major depressive disorder, using seed-based resting-state functional connectivity in 50 medication-free patients with adolescent-onset major depressive disorder and 56 healthy controls. Irrespective of sex, compared with healthy controls, adolescent-onset major depressive disorder patients showed hypoconnectivity between bilateral hippocampus and right superior temporal gyrus (default mode network). More importantly, we further found that females with adolescent-onset major depressive disorder exhibited hypoconnectivity within the default mode network (medial prefrontal cortex), and between the subcortical regions (i.e. amygdala, striatum, and thalamus) with the default mode network (angular gyrus and posterior cingulate cortex) and the frontoparietal network (dorsal prefrontal cortex), while the opposite patterns of resting-state functional connectivity alterations were observed in males with adolescent-onset major depressive disorder, relative to their sex-matched healthy controls. Moreover, several sex-specific resting-state functional connectivity changes were correlated with age of onset, sleep disturbance, and anxiety in adolescent-onset major depressive disorder with different sex. These findings suggested that these sex-specific resting-state functional connectivity alterations may reflect the differences in brain development or processes related to early illness onset, underscoring the necessity for sex-tailored diagnostic and therapeutic approaches in adolescent-onset major depressive disorder.

Study of a PST-trained voice-enabled artificial intelligence counselor for adults with emotional distress (SPEAC-2): Design and methods

BackgroundNovel and scalable psychotherapies are urgently needed to address the depression and anxiety epidemic. Leveraging artificial intelligence (AI), a voice-based virtual coach named Lumen was developed to deliver problem solving treatment (PST). The first pilot trial showed promising changes in cognitive control measured by functional neuroimaging and improvements in depression and anxiety symptoms. MethodsTo further validate Lumen in a 3-arm randomized clinical trial, 200 participants with mild-to-moderate depression and/or anxiety will be randomly assigned in a 2:1:1 ratio to receive Lumen-coached PST, human-coached PST as active treatment comparison, or a waitlist control condition where participants can receive Lumen after the trial period. Participants will be assessed at baseline and 18 weeks. The primary aim is to confirm neural target engagement by testing whether compared with waitlist controls, Lumen participants will show significantly greater improvements from baseline to 18 weeks in the a priori neural target for cognitive control, right dorsal lateral prefrontal cortex engaged by the go/nogo task (primary superiority hypothesis). A secondary hypothesis will test whether compared with human-coached PST participants, Lumen participants will show equivalent improvements (i.e., noninferiority) in the same neural target from baseline to 18 weeks. The second aim is to examine (1) treatment effects on depression and anxiety symptoms, psychosocial functioning, and quality of life outcomes, and (2) relationships of neural target engagement to these patient-reported outcomes. ConclusionsThis study offers potential to improve the reach and impact of psychotherapy, mitigating access, cost, and stigma barriers for people with depression and/or anxiety.Clinicaltrials.gov #: NCT05603923

Bilingual Language Control in the Brain: Evidence from Structural and Effective Functional Brain Connectivity.

Experience in bilingual language control is often accompanied by changes in the structure and function of the brain. Brain structural changes are also often closely related to changes in functions. Previous studies, however, have not directly explored the relationship between structural connectivity and effective functional connectivity of the brain during bilingual language control, and whether the two types of connectivity are associated with behavioral performance of language control. Using behavioral performance, functional, and diffusion imaging techniques, we found that: (1) during language control, the left dorsal lateral prefrontal cortex (dlPFC), left caudate nucleus (CN), inferior parietal lobe, precuneus, and dorsal anterior cingulate cortex (dACC)/pre-SMA were significantly activated. (2) In the language control model with left dlPFC, dACC/pre-SMA, and left CN as ROIs (selected based on activation results and language control models from previous studies), stimuli first enter dACC/pre-SMA and then to left CN. At the left CN, a bidirectional effective connectivity is formed with left dlPFC. (3) There is a nonlinear relationship between effective connectivity during language control and the structural connectivity of the second language learners' brains. Specifically, the fiber density between dACC/pre-SMA and left dlPFC has a positive influence on the bidirectional effective connectivity between left dlPFC and left CN. Findings of the present study contribute evidence toward functional effective connectivity during bilingual language control; toward structural connectivity in the brains of second language learners; as well as toward nonlinear relationships between functional effective connectivity, structural connectivity, and behavioral performance in relation to bilingual language control.

Inspiratory Pressure Threshold Loading: Effects on Inspiratory Pattern, Perception and Prefrontal Cortical Activity

Cognitive awareness of breathing can lead to behavioral ventilatory compensation, respiratory interoception and activation of brain regions associated with decision processes, including the dorsal prefrontal cortex (dPFC). The dPFC is a critical cortical region mediating executive functions and dPFC activity is modulated during increased breathing load. This study investigated load compensation and perception response to sustained breathing against inspiratory pressure threshold (PT) loads. We hypothesized that increasing magnitudes of PT loads require increasing time to valve opening resulting in; greater inspiratory motor drive, increased perception of breathing effort (INT), increased perception of unpleasantness (UPL) and increased dPFC oxygen consumption (OXY, a measure of increased neural activity). Functional near-infrared spectroscopy (fNIRS) was used to measure OXY changes in the dPFC. Healthy subjects were exposed to 5 cmH2O (LoPT) and 20 cmH2O (HiPT) inspiratory PT loads for 1 minute load-on and 1 minute load-off trials. A total of 8 trials for each load were presented, 4 INT trials and 4 UPL trials. Perception of inspiratory INT and UPL was rated with a 0-10 modified Borg scale. There was a significant PT magnitude dependent increase in valve opening duration (0.18±0.15 LoPT vs 0.57±0.17 HiPT) and pressure (-4.4±0.75 LoPT vs -21.3±2.2 HiPT, p<0.001). The pressure-time-product (PtP), a measure of inspiratory motor drive, significantly (p<0.001) increased with PT magnitude. A significant PT magnitude dependent increase in INT (2.8±1.3 vs 7.9±1.2, p<0.001) and UPL (1.9±1.4 vs 7.8±1.4, p<0.001) ratings occurred but perception ratings did not significantly change throughout the 1-minute trial. The average 1-minute trial OXY LoPT was significantly (p<0.02) less than HiPT. The right dPFC OXY did not significantly change between trial Breath 1 and Breath 10. The left dPFC OXY significantly (p<0.01) increased from trial Breath 1 to Breath 10. These results suggest increased PT load magnitude required greater inspiratory drive to breathe. Breathing against a HiPT load was perceived as highly effortful and unpleasant. Sustained breathing against PT loads progressively increased left dPFC neural activity. Supported by the University of Florida, College of Veterinary Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glycoproteome-Wide Discovery of Cortical Glycoproteins That May Provide Cognitive Resilience in Older Adults.

Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience. We studied brains from adults with annual cognitive testing with postmortem indices of 10 AD/ADRD pathologies and proteome-wide data from dorsal lateral prefrontal cortex (DLPFC). We quantified 11, 012 glycopeptiforms from DLPFC using liquid chromatography with tandem mass spectrometry. We used linear mixed-effects models to identify glycopeptiforms associated with cognitive decline correcting for multiple comparisons (p < 5 × 10-6). Then, we regressed out the effect of AD/ADRD pathologies to identify glycopeptiforms that may provide cognitive resilience. We studied 366 brains, average age at death 89 years, and 70% female with no cognitive impairment = 152, mild cognitive impairment = 93, and AD = 121 cognitive status at death. In models adjusting for age, sex and education, 11 glycopeptiforms were associated with cognitive decline. In further modeling, 8 of these glycopeptiforms remained associated with cognitive decline after adjusting for AD/ADRD pathologies: NPTX2a (Est., 0.030, SE, 0.005, p = 1 × 10-4); NPTX2b (Est.,0.019, SE, 0.005, p = 2 × 10-4) NECTIN1(Est., 0.029, SE, 0.009, p = 9 × 10-4), NPTX2c (Est., 0.015, SE, 0.004, p = 9 × 10-4), HSPB1 (Est., -0.021, SE, 0.006, p = 2 × 10-4), PLTP (Est., -0.027, SE, 0.009, p = 4.2 × 10-3), NAGK (Est., -0.027, SE, 0.008, p = 1.4 × 10-3), and VAT1 (Est., -0.020, SE, 0.006, p = 1.1 × 10-3). Higher levels of 4 resilience glycopeptiforms derived through glycosylation were associated with slower decline and higher levels of 4 derived through glycation were related to faster decline. Together, these 8 glycopeptiforms accounted for an additional 6% of cognitive decline over the 33% accounted for the 10 brain pathologies and demographics. All 8 resilience glycopeptiforms remained associated with cognitive decline after adjustments for the expression level of their corresponding protein. Exploratory gene ontology suggested that molecular mechanisms of glycopeptiforms associated with cognitive decline may involve metabolic pathways including pyruvate and NADH pathways and highlighted the importance of molecular mechanisms involved in glucose metabolism. Glycopeptiforms in aging brains may provide cognitive resilience. Targeting these glycopeptiforms may lead to therapies that maintain cognition through resilience.

Acute stress impairs intentional memory suppression through aberrant prefrontal cortex activation in high trait ruminators

ObjectiveResearch shows that the effect of acute stress on intentional memory suppression could be modulated by individual differences in psychological traits. However, whether acute stress distinctly affects intentional memory suppression in high trait ruminators, a high at-risk group of stress-related disorders, and the neural correlations, remains unclear. Method55 healthy college students were divided into high and low trait ruminators (HTR and LTR), Following stress manipulation, a Think/No Think task assessed the memory suppression performance. Functional near-infrared spectroscopy was applied to explore the neural correlates. Psychophysiological interaction analyses were used to assess how the functional connectivity between a seed region and another brain region was modulated by tasks during memory suppression, further mediating memory suppression performance and state rumination. ResultsThe HTR exhibited poorer memory suppression performance than the LTR under the stress condition. Aberrant activation patterns and task-modulated functional connectivity in the dorsal prefrontal cortex (DLPFC) and superior temporal gyrus (STG) were observed only in the HTR during memory suppression under the stress condition. The effect of memory suppression performance on the state rumination of individuals was significantly mediated by the task-modulated functional connectivity between the DLPFC and STG. ConclusionsThe findings could provide insights for prevention or early intervention in the development of stress-related disorders in HTR.

Transcranial Direct Current Stimulation (tDCS) as a Therapeutic Tool for Chronic Insomnia

&#x0D; &#x0D; &#x0D; &#x0D; Background and Objective: Insomnia is the most common sleep problem which is associated with cortical over- excitation. Transcranial direct-current stimulation (tDCS) potentially modifies insomnia-related cortical state. There- fore, we tested the hypothesis that insomnia severity can be modulated by tDCS.&#x0D; Materials and Methods: The current study was conducted with a pretest-posttest design and a control group. A total of 32 women with insomnia were randomly categorized into an intervention group (active stimulation) and a control group (sham stimulation). In the intervention group, tDCS ‎was used with an intensity of 2mA for 20 to 30 minutes during 12 sessions (3 times a week). Anodal stimulation was performed‎on the left primary motor cortex (M1) and cathodal stimulation was performed‎on the right dorsal lateral prefrontal cortex (DLPFC). The control group received sham stim- ulation for 20 to 30 minutes during 12 sessions (3 times a week). All participants were evaluated before and after the intervention using the Insomnia Severity Index (ISI) and Positive Affect and Negative Affect Schedule (PANAS).&#x0D; Results: The results of univariate analysis of covariance (ANCOVA) and multivariate analysis of covariance (MANCOVA) showed a significant difference between the tDCS group and the sham group in terms of reduction in the severity of insomnia. We also observed that positive affect increased and negative affect decreased following insomnia treatment (P ≤ 0.005).&#x0D; Conclusion: The results of our study indicated that performing our designed tDCS protocol for treating insomnia can be effective in treating insomnia and improving positive and negative affect.&#x0D; &#x0D; &#x0D; &#x0D;

Serotonergic modulation of vigilance states in zebrafish and mice

Vigilance refers to being alertly watchful or paying sustained attention to avoid potential threats. Animals in vigilance states reduce locomotion and have an enhanced sensitivity to aversive stimuli so as to react quickly to dangers. Here we report that an unconventional 5-HT driven mechanism operating at neural circuit level which shapes the internal state underlying vigilance behavior in zebrafish and male mice. The neural signature of internal vigilance state was characterized by persistent low-frequency high-amplitude neuronal synchrony in zebrafish dorsal pallium and mice prefrontal cortex. The neuronal synchronization underlying vigilance was dependent on intense release of 5-HT induced by persistent activation of either DRN 5-HT neuron or local 5-HT axon terminals in related brain regions via activation of 5-HTR7. Thus, we identify a mechanism of vigilance behavior across species that illustrates the interplay between neuromodulators and neural circuits necessary to shape behavior states.

Towards a Real-Life Understanding of the Altered Functional Behaviour of the Default Mode and Salience Network in Chronic Pain: Are People with Chronic Pain Overthinking the Meaning of Their Pain?

Chronic pain is a source of substantial physical and psychological suffering, yet a clear understanding of the pathogenesis of chronic pain is lacking. Repeated studies have reported an altered behaviour of the salience network (SN) and default mode network (DMN) in people with chronic pain, and a majority of these studies report an altered behaviour of the dorsal ventromedial prefrontal cortex (vmPFC) within the anterior DMN. In this topical review, we therefore focus specifically on the role of the dorsal vmPFC in chronic pain to provide an updated perspective on the cortical mechanisms of chronic pain. We suggest that increased activity in the dorsal vmPFC may reflect maladaptive overthinking about the meaning of pain for oneself and one's actions. We also suggest that such overthinking, if negative, may increase the personal "threat" of a given context, as possibly reflected by increased activity in, and functional connectivity to, the anterior insular cortex within the SN.

Dl-3-n-Butylphthalide Alleviates Secondary Brain Damage and Improves Working Memory After Stroke in Cynomolgus Monkeys.

Remote secondary neurodegeneration is associated with poststroke cognitive impairment (PSCI). Dl-3-n-butylphthalide (NBP) improves PSCI clinically. However, whether it ameliorates PSCI by alleviating secondary neurodegeneration remains uncertain. Nonhuman primates provide more relevant models than rodents for human stroke and PSCI. This study investigated the effects of NBP on PSCI and secondary neurodegeneration in cynomolgus monkeys after permanent left middle cerebral artery occlusion (MCAO). Thirteen adult male cynomolgus monkeys were randomly assigned to sham (n=4), MCAO+placebo (n=5), and MCAO+NBP groups (n=4). The MCAO+placebo and MCAO+NBP groups received saline and NBP injections intravenously, respectively, starting at 6-hour postsurgery for 2 weeks, followed by soybean oil and NBP orally, respectively, for 10 weeks after MCAO. Infarct size was assessed at week 4 by magnetic resonance imaging. Working memory and executive function were evaluated dynamically using the delayed response task and object retrieval detour task, respectively. Neuron loss, glia proliferation, and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex, thalamus, and hippocampus were analyzed by immunostaining 12 weeks after MCAO. Infarcts were located in the left middle cerebral artery region, apart from the ipsilateral dorsal lateral prefrontal cortex, thalamus, or hippocampus, with no significant difference between the MCAO+placebo and MCAO+NBP group. Higher success in delayed response task was achieved at weeks 4, 8, and 12 after NBP compared with placebo treatments (P<0.05), but not in the object retrieval detour task (all P>0.05). More neurons and less microglia, astrocytes, CD68-positive microglia, tumor necrosis factor-α, and inducible NO synthase were observed in the ipsilateral dorsal lateral prefrontal cortex and thalamus after 12 weeks of NBP treatment (P<0.05), but not in the hippocampus (P>0.05). Our findings indicate that NBP improves working memory by alleviating remote secondary neurodegeneration and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex and thalamus after MCAO in cynomolgus monkeys.

Brain connectivity changes to fast versus slow dopamine increases

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = −0.54, pspin < 0.001). GBC showed “fast>slow” associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and “slow>fast” associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). “Fast>slow” GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported ‘high’ ratings to intravenous MP across individuals (r(19) = −0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Effect of immersive virtual reality-based cognitive remediation in patients with mood or psychosis spectrum disorders: study protocol for a randomized, controlled, double-blinded trial

BackgroundCognitive impairments are prevalent across mood disorders and psychosis spectrum disorders, but there is a lack of real-life-like cognitive training programmes. Fully immersive virtual reality has the potential to ensure motivating and engaging cognitive training directly relevant to patients’ daily lives. We will examine the effect of a 4-week, intensive virtual reality-based cognitive remediation programme involving daily life challenges on cognition and daily life functioning in patients with mood disorders or psychosis spectrum disorders and explore the neuronal underpinnings of potential treatment efficacy.MethodsThe trial has a randomized, controlled, double-blinded, parallel-group design. We will include 66 symptomatically stable outpatients with mood disorders or psychosis spectrum disorders aged 18–55 years with objective and subjective cognitive impairment. Assessments encompassing a virtual reality test of daily life cognitive skills, neuropsychological testing, measures of daily life functioning, symptom ratings, questionnaires on subjective cognitive complaints, and quality of life are carried out at baseline, after the end of 4 weeks of treatment and at a 3-month follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and at the end of treatment. The primary outcome is a broad cognitive composite score comprising five subtasks on a novel ecologically valid virtual reality test of daily life cognitive functions. Two complete data sets for 54 patients will provide a power of 80% to detect a clinically relevant between-group difference in the primary outcome. Behavioural data will be analysed using linear mixed models in SPSS, while MRI data will be analysed with the FMRIB Expert Analysis Tool (FEAT). Treatment-related changes in neural activity from baseline to end of treatment will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest.DiscussionThe results will provide insight into whether virtual reality-based cognitive remediation has beneficial effects on cognition and functioning in symptomatically stable patients with mood disorders or psychosis spectrum disorders, which can aid future treatment development.Trial registrationClinicalTrials.gov NCT06038955. Registered on September 15, 2023.