Prefrontal Cortex Research Articles

High definition transcranial direct current stimulation as an intervention for cognitive deficits in Alzheimer's dementia: A randomized controlled trial.

Recent disease-modifying treatments for Alzheimer's disease show promise to slow cognitive decline, but show no efficacy towards reducing symptoms already manifested. To investigate the efficacy of a novel noninvasive brain stimulation technique in modulating cognitive functioning in Alzheimer's dementia (AD). Pilot, randomized, double-blind, parallel, sham-controlled study SETTING: Clinical research site at UT Southwestern Medical Center PARTICIPANTS: Twenty-five participants with clinical diagnoses of AD were enrolled from cognition specialty clinics. Treatment consisted of high definition transcranial direct current stimulation (HD-tDCS) delivered for 20 min over the medial prefrontal cortex. Ten sessions of sham, 1 mA, or 2 mA stimulation were received. Cognitive outcomes were measured at baseline, after the last HD-tDCS session, and 8-weeks post-treatment. The primary outcome was change in total learning and delayed recall on the Rey Auditory Verbal Learning Test (RAVLT) immediately post-treatment and at 8-weeks. Secondary outcomes included measures of language, processing speed, and executive functioning. A multi-stage approach was used to examine cognitive outcomes, which included evaluation of effect sizes, statistical effects, and rate of clinically meaningful responses. In this pilot trial, no statistically significant differences on cognitive outcomes were found between sham and active HD-tDCS immediately post-treatment (p's > 0.05). However, moderate-to-large effect sizes were identified for enhanced RAVLT total learning (Cohen's d = 0.69-0.93) and phonemic fluency (d = 1.08-1.49) for both active HD-tDCS conditions compared to sham, with rates of clinically relevant improvement between 25 and 33%. Meaningful enhancement persisted to 8 weeks only for the 1 mA condition. Multiple sessions of HD-tDCS over the medial prefrontal cortex appears to have potential to produce meaningful cognitive enhancements in a proportion of patients having AD with improvements maintained for at least 8 weeks in some. ClinicalTrials.gov (NCT05270408). Registered December 30, 2021.

Repeated social defeat in male mice induced unique RNA profiles in projection neurons from the amygdala to the hippocampus

Chronic stress increases the incidence of psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Repeated Social Defeat (RSD) in mice recapitulates several key physiological, immune, and behavioral changes evident after chronic stress in humans. For instance, neurons in the prefrontal cortex, amygdala, and hippocampus are involved in the interpretation of and response to fear and threatful stimuli after RSD. Therefore, the purpose of this study was to determine how stress influenced the RNA profile of hippocampal neurons and neurons that project into the hippocampus from threat appraisal centers. Here, RSD increased anxiety-like behavior in the elevated plus maze and reduced hippocampal-dependent novel object location memory in male mice. Next, pan-neuronal (Baf53b-Cre) RiboTag mice were generated to capture ribosomal bound mRNA (i.e., active translation) activated by RSD in the hippocampus. RNAseq revealed that there were 1,694 differentially expressed genes (DEGs) in hippocampal neurons after RSD. These DEGs were associated with an increase in oxidative stress, synaptic long-term potentiation, and neuroinflammatory signaling. To further examine region-specific neural circuitry associated with fear and anxiety, a retrograde-adeno-associated-virus (AAV2rg) expressing Cre-recombinase was injected into the hippocampus of male RiboTag mice. This induced expression of a hemagglutinin epitope in neurons that project into the hippocampus. These AAV2rg-RiboTag mice were subjected to RSD and ribosomal-bound mRNA was collected from the amygdala for RNA-sequencing. RSD induced 677 DEGs from amygdala projections. Amygdala neurons that project into the hippocampus had RNA profiles associated with increased synaptogenesis, interleukin-1 signaling, nitric oxide, and reactive oxygen species production. Using a similar approach, there were 1,132 DEGs in neurons that project from the prefrontal cortex. These prefrontal cortex neurons had RNA profiles associated with increased synaptogenesis, integrin signaling, and dopamine feedback signaling after RSD. Collectively, there were unique RNA profiles of stress-influenced projection neurons and these profiles were associated with hippocampal-dependent behavioral and cognitive deficits.

Amelioration of gap junction dysfunction in a depression model by loganin: Involvement of GSK-3β/β-catenin signaling.

Cornus officinalis Sieb. et Zucc has significant neuroprotective activity and has been widely studied for its potential to improve cognitive function. Our team's previous research has found that loganin isolated from Cornus officinalis has an antidepressant effect. Depression is a mental disorder accompanied by dysfunction of Connexin43 (Cx43)-formed astrocytic gap junctions. However, the precise mechanisms of loganin involved remain uncertain. We aimed to examine the mechanism by which loganin produces its antidepressant properties. Using a chronic unpredictable stress (CUS) model of depression in rats, the study evaluated the behavioral responses to treatment with loganin, fluoxetine, and their combination. Biochemical analyses were conducted to measure the expression and phosphorylation status of Cx43, β-catenin, GSK-3β in the brain. In vitro experiments were also performed how loganin protects the gap junctions in astrocytes that have been exposed to corticosterone. After four weeks of loganin treatment, rats exposed to CUS showed a decrease in depressive-like behaviors. When combined with fluoxetine, the antidepressant-like effects were observed faster than with either treatment alone. Loganin significantly increased Cx43 expression in the prefrontal cortex and ventral hippocampus, reversed Cx43 mimetic peptide Gap26-induced depressive-like behaviors, decreased Cx43 phosphorylation at Ser368, increased β-catenin levels, and promoted GSK-3β phosphorylation at Ser9. In vitro, loganin prevented corticosterone-induced damage to gap junctions between astrocytes, an effect that was negated by XAV-939 (β-catenin inhibitor). These results implied that loganin could exert antidepressant-like effects by improving the gap junctions of astrocytes in the prefrontal cortex and hippocampus, acting through the GSK-3β/β-catenin signaling pathway. The combination of loganin with fluoxetine may provide a faster onset of antidepressant action compared to either treatment alone, highlighting the potential of loganin as a natural adjunct therapy for depression.

Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates transcripts important for anxiolytic-like behavior

We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents reductions in sociability normally caused by stress. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and increases social avoidance, particularly in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used to promote social behavior and, potentially, relieve symptoms of social anxiety. S1PR3 might be an important hub gene for mitigating maladaptive effects of stress as it reduces inflammatory processes, increases transcripts linked to anxiolytic neurotransmission, and promotes social behavior.

Corticosteroid receptor antagonism in the medial prefrontal cortex reduces morphine-induced place preference and dopamine transporter expression decline in rats.

Corticosteroid signaling plays a critical role in modulating the neural systems underlying reward and addiction, but the specific contributions of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the medial prefrontal cortex (mPFC) to opioid reward and dopaminergic plasticity remain unclear. Here, we investigated the effects of intra-mPFC injection of corticosteroid receptor ligand (corticosterone; CORT), glucocorticoid receptor antagonist (RU38486; RU), and mineralocorticoid receptor antagonist (spironolactone; SP) on morphine-induced conditioned place preference (CPP) and dopamine transporter (DAT) expression in the mPFC. Adult male Wistar rats received intra-mPFC injections of CORT, RU, SP, or their respective vehicles prior to morphine CPP conditioning. Blockade of GRs with RU (10 or 100ng) or MRs with a low dose of SP (10ng) attenuated the expression of morphine CPP. Morphine reduced DAT expression in the mPFC, but RU and SP prevented this effect. These findings demonstrate that corticosteroid receptor signaling within the mPFC modulates the rewarding properties of morphine and morphine-induced dopaminergic plasticity. This preclinical study suggests that targeting GRs and MRs in the mPFC could be a possible therapeutic approach for treating opioid addiction. By targeting these receptors, it may be possible to reduce opioid reward and counteract the neuroadaptations in dopamine systems associated with addiction.

Caffeine intake during gestation and lactation causes long-term behavioral impairments in heterogenic mice offspring in a sex-dependent manner.

Growing evidence has indicated a potential association between maternal consumption of caffeine and impaired cognition and behavior in rodent offspring. However, potential sex differences, as well as caffeine-related effects in subsequent generations are still poorly investigated. We aimed to investigate the impact of pre-and/or neonatal exposition to caffeine on the neurodevelopment of male and female mice offspring. Adult female Swiss mice were randomly divided into four experimental groups, which received, via gavage, water or caffeine (120mg/day). Control/control (CC) received water during pregnancy and lactation; treated/control (TC): received caffeine during pregnancy and water during lactation; control/treated (CT): received water during pregnancy and caffeine during lactation; treated/treated (TT): received caffeine during pregnancy and lactation. Dams were euthanized at gestational day 17.5 and fetal brains were collected. Adult mice of F1 and F2 generations were submitted to behavioral analysis and their pre-frontal cortex and hippocampi were dissected to measure the levels of BDNF and CX3CL1. Caffeine induced reduction of CX3CL1 levels in female fetuses compared with controls. Maternal intake of caffeine was associated with anxiety- and compulsive-like behavior in both F1 and F2 female mice offspring. Interestingly, only F2 female mice exhibited caffeine-induced impairment of work memory. Hippocampal levels of CX3CL1 and BDNF were decreased in female F1TT and F2TT groups; while among males exposed to caffeine, only F1 offspring had reduced hippocampal CX3CL1 levels. Our results suggest that both pre- and neonatal exposition to caffeine lead to long-term behavioral and neurochemical impairments in a sex-dependent manner, adversely affecting the subsequent female generation.

An insight from the default mode network in patients with amnesia following left thalamic infarction involving the mediodorsal nucleus and mammillothalamic tract.

The role of the medial part of the thalamus, and in particular the mediodorsal nucleus (MD) and the mammillothalamic tract (MTT), in memory has long been studied, but their contribution remains unclear. While the main functional hypothesis regarding the MTT focuses on memory, some authors postulate that the MD plays a supervisory executive role (indirectly affecting memory retrieval) due to its dense structural connectivity with the prefrontal cortex (PFC). Recently, it has been proposed that the MD, MTT and PFC form part of the DMN the default mode network (DMN). Due to the theoretical presence of MD and MTT in the DMN, we aimed to show the effect of thalamic lesions on functional connectivity (FC) and its putative role in cognitive impairment. We recruited 12 patients with left thalamic infarction and 12 matched healthy controls. They underwent neuropsychological assessment including memory tasks, morphological 3D MRI and resting state fMRI. A ROI-to-ROI method was used for group-level FC analyses. Patients had lesions in the MD and ventrolateral nuclei, with a damaged mammillothalamic tract (MTT) in seven of them. They showed lower performance than controls on verbal memory, executive function and language tests, with more impairment in memory, working memory, semantic verbal fluency and attention in the MTT-damaged patients. Contrast analyses between patients and matched controls showed lower FC in the ventral and dorsal DMN. Correlation analyses (patients and controls pooled) showed i/a positive correlation between memory and DMN, and ii/that MTT volume correlated with decreased functional connectivity in the dorsal DMN, whereas there was no correlation with MD lesion volume. These results suggest that both the memory impairment and the DMN functional change we observed may reflect an effect of the MTT lesion rather than MD damage.

Distinct Effects of Olanzapine Depot Treatment on Behavior and Muscarinic M1 Receptor Expression in the Triple-Hit Wisket Rat Model of Schizophrenia.

This study aimed to characterize the triple-hit schizophrenia-like model rats (Wisket) by the assessment of (1) behavioral parameters in different test conditions (reward-based Ambitus test and HomeManner system) for a prolonged period, (2) cerebral muscarinic M1 receptor (M1R) expression, and (3) the effects of olanzapine treatment on these parameters. Wistar (control) and Wisket rats were injected for three consecutive weeks with olanzapine depot (100 mg/kg) and spent 4 weeks in large cages with environmental enrichment (HomeManner). The vehicle-treated Wisket rats spent longer time awake with decreased grooming activity compared to controls, without changes in their active social behavior (sniffing, playing, fighting) obtained in HomeManner. Olanzapine treatment decreased most of these parameters, only the passive social interaction (huddling during sleeping) enhanced mostly in the Wisket rats on the injection day, which recovered within 4 days. In the Ambitus test, vehicle-treated Wisket rats showed lower locomotor and exploratory activities and impaired cognition compared to control rats, deteriorating by olanzapine in both groups. In Wisket brain samples, the M1R mRNA expression was significantly lower in the cerebral cortex and elevated in the hippocampus, with no difference in the prefrontal cortex versus control. Olanzapine normalized the hippocampal M1R expression, but enhanced it in the prefrontal cortex. The triple-hit Wisket model rats had impaired behavioral characteristics in both acute reward-based test and undisturbed circumstances investigated for prolonged periods, and altered cerebral M1R expression. Chronic olanzapine treatment resulted deterioration of some parameters in control group, and could restore only few negative signs in model rats.

Electroacupuncture and Tongbian decoction ameliorate CUMS-induced depression and constipation in mice via TPH2/5-HT pathway of the gut-brain axis.

Depression is commonly associated with gastrointestinal (GI) disorders, such as constipation, which can potentially intensify depressive symptoms. The interplay between these conditions is believed to be facilitated by the gut-brain axis, which suggests a complex bidirectional interaction. Current treatments, such as antidepressants and prokinetics, are often associated with side effects and high recurrence rates, highlighting the need for effective treatments targeting both depression and constipation. This study was designed to assess the therapeutic efficacy of electroacupuncture (EA) in conjunction with Tongbian decoction (TB) for the management of both depression and constipation, while also investigating the underlying mechanisms through the lens of the gut-brain axis. Chronic unpredictable mild stress (CUMS) was employed to induce a comorbidity model of depression and constipation in mice, followed by the administration of EA, EA + TB, and fluoxetine (FLX). The findings of the study demonstrated that the antidepressant effects of electroacupuncture (EA) in combination with Tongbian decoction (TB) were more pronounced than those of EA alone. The EA + TB treatment significantly ameliorated depression and anxiety-like behaviors, restored cognitive function, and enhanced gastrointestinal motility in chronic unpredictable mild stress (CUMS) mice. Furthermore, EA + TB reduced intestinal inflammation, restored neuronal morphology, increased the expression of tryptophan hydroxylase 2 (TPH2) in both the prefrontal cortex (PFC) and colon, elevated the serum levels of 5-hydroxytryptophan (5-HTP)-a molecule that acts as a gut-brain connector-and promoted the synthesis and production of serotonin (5-HT) in both the gastrointestinal tract and the brain. Contrastingly, FLX showed limited efficacy in improving constipation. In conclusion, EA + TB regulates the TPH2/5-HT pathway via the gut-brain axis, demonstrating synergistic regulation of the nervous and gastrointestinal systems, with favorable antidepressant and prokinetic effects.

Current source density and functional connectivity extracted from resting-state electroencephalography as biomarkers for chronic low back pain.

Chronic low back pain (CLBP) is a global health issue, and its nonspecific causes make treatment challenging. Understanding the neural mechanisms of CLBP should contribute to developing effective therapies. To compare current source density (CSD) and functional connectivity (FC) extracted from resting electroencephalography (EEG) between patients with CLBP and healthy controls and to examine the correlations between EEG indices and symptoms. Thirty-four patients with CLBP and 34 healthy controls in an open data set were analyzed. Five-minute resting-state closed-eye EEG was acquired using the international 10-20 system. Current source density across frequency bands was calculated using exact low-resolution electromagnetic tomography. Functional connectivity was assessed between 24 cortical regions using lagged linear connectivity. Correlations between pain symptoms and CSD distribution and FC were examined in patients with CLBP. Current source density analysis showed no significant differences between the groups. The CLBP group exhibited significantly reduced FC in the β3 band between the left middle temporal gyrus and the posterior cingulate cortex, and between the ventral medial prefrontal cortex and the left inferior parietal lobule. Prefrontal θ and δ activity positively correlated with pain symptoms. Increased β1 band FC between the right dorsolateral prefrontal cortex and right auditory cortex correlated with greater pain intensity. We found altered neural activity and connectivity in patients with CLBP, particularly in prefrontal and temporal regions. These results suggest potential targets for pain modulation through brain pathways and highlight the value of EEG biomarkers in understanding pain mechanisms and assessing treatment efficacy.

Region-specific neuroadaptations of CRF1 and CRF2 expression following heroin exposure in female rats

While stress increases vulnerability to development of addiction, the recruitment of corticotropin releasing factor (CRF) with excessive drug use heightens the risk of stress-induced relapse. CRF signaling is transmitted via CRF1 and CRF2 receptors, but the roles of these receptors in heroin self-administration and related neuroadaptations of the CRF system within mesolimbic brain loci are not well understood. In this study, we first investigated the causal role of CRF1 and CRF2 receptors in heroin self-administration. Intracerebroventricular (ICV) microinjections of antalarmin (a CRF1 antagonist) or astressin-2B (a CRF2 antagonist) caused brief, dose-dependent reductions in heroin self-administration in female rats, suggesting that these receptors play a critical role in heroin-motivated behaviors. We then used western blotting to examine neuroadaptive changes to CRF1 and CRF2 receptor expression in key forebrain and midbrain regions associated with opioid addiction. Female Long Evans rats treated with escalating doses of heroin for 16 days demonstrated significantly higher naloxone-precipitated withdrawal symptoms than saline-treated rats. Heroin-treated rats showed a significant decrease in CRF1 receptor protein expression in the ventral tegmental area (VTA) and an increase in the nucleus accumbens (NAc) but no changes in the prefrontal cortex (PFC), insula, dorsal striatum (dSTR), dorsal hippocampus (dHippo), anterior hypothalamus (HYPTH), amygdala, or substantia nigra (SN) as compared to saline-treated rats. After chronic heroin exposure, CRF2 receptor expression was significantly downregulated in the dHippo, VTA and HYPTH but not in the other brain regions we investigated. The results of this study suggest that: (1) CRF1 and CRF2 receptors play an important role in self-administration and (2) heroin exposure may lead to region-specific neuroadaptation of CRF1 and CRF2 receptors. Such neuroadaptations might in part contribute to the continuation of drug use and stress-induced relapse.

Chlorpyrifos intermittent exposure enhances cardiovascular but not behavioural responses to contextual fear conditioning in adult rats: possible involvement of brain oxidative-nitrosative stress

Exposure to organophosphorus compounds (OPs) may cause psychiatric, neurologic, biochemical, and cardiovascular abnormalities. Neurotoxicity of OP compounds is primarily due to irreversibly inhibition of the acetylcholinesterase (AChE) enzyme both centrally and peripherally. Chlorpyrifos (CPF) is a widely used OP classified as moderately toxic. Previously, it has been shown that CPF administration, given every other day to adult rats, impairs spatial memory and prepulse inhibition associated with brain AChE inhibition. Our group also found that intermittent treatment with CPF, simulating occupational exposure, impairs the cardiorespiratory reflexes and causes cardiac hypertrophy. Thereby, we aimed to examine whether subchronic and intermittent administration of CPF would affect the behavioural (freezing) and cardiovascular (mean arterial pressure, MAP; heart rate, HR) responses elicited during contextual fear conditioning (CFC) and extinction. Wistar adult male rats were injected with sublethal and intermittent CPF doses (4 and 7mg/kg) three times a week for one month. Two days after the last injection, a range of tests were performed to assess depression (sucrose preference), anxiety (elevated plus-maze, EPM), locomotion (open field, OF), and conditioned fear expression and extinction. Separate cohorts of animals were euthanized to measure plasma butyrylcholinesterase (BChE), erythrocyte AChE, brain AChE activity, and markers of oxidative-nitrosative stress. Intermittent CPF treatment did not affect sucrose preference. CPF (4 and 7mg/kg) reduced open-arms exploration in the EPM, suggesting an anxiogenic effect. The higher dose of CPF decreased the total distance travelled in the OFT, suggesting motor impairment. After a seven-day CPF-free washout period, CPF (7mg/kg) increased the tachycardic response without affecting freezing behaviour in the CFC extinction session. CPF 7mg/kg decreased AChE activity in the hippocampus, pre-frontal cortex and brainstem 72 after the last administration whilst transiently increasing oxidative-nitrosative stress specifically in the brainstem. Overall, our results outlined the behavioural, autonomic and biochemical abnormalities caused by an intermittent dosing regimen of CPF that elicits brain AChE inhibition and brain oxidative-nitrosative stress. This paradigm might be valuable in further exploring long-term consequences and mechanisms of OP neurotoxicity as well as comprehensive therapeutic approaches.

Peripartum buprenorphine and oxycodone exposure impair maternal behavior and increase neuroinflammation in the brains of new mother rats

7% of pregnant people use opioids. Opioid use during pregnancy can negatively impact maternal and offspring health. Medications for opioid use disorder (MOUD), commonly buprenorphine, are the recommended treatment for opioid use disorder during pregnancy to prevent cycles of withdrawal and relapse. In addition to effects on opioid receptors, opioids have strong binding affinity to toll like receptor (TLR) 4, an immune cell receptor, and thereby impact neuroinflammatory signaling. We have previously shown that neuroimmune alterations are important for the display of maternal behavior. Here, we used a rodent model to assess the impact of chronic peripartum opioid exposure or MOUD on maternal caregiving and neuroinflammation in the postpartum brain. Female rats were exposed to vehicle (VEH), buprenorphine (BUP) to model MOUD, or oxycodone (OXY), before, during, and after pregnancy. Opioid exposure reduced gestation length and maternal weight gain. Postpartum maternal caretaking behaviors, including pup retrieval, huddling and nursing, and pup-directed sniffing and licking, were reduced in opioid-exposed mothers. Following behavioral testing, tissue was collected from brain regions important for maternal caretaking, including the prefrontal cortex (PFC), nucleus accumbens (NAc), preoptic area (POA), and periaqueductal grey (PAG). Immunofluorescent labeling showed that BUP increased astrocyte labeling, while OXY increased microglia labeling in the PAG, but not other regions. Gene expression analysis also showed regional and treatment differences in immune transcripts. BUP and OXY increased TLR4 in the PFC. BUP increased TNF in the NAc but decreased IL1β in the POA. OXY increased CD68 in the POA, and IL1β, TNF, and TLR4 in the PAG. Together, these results provide novel evidence of peripartum neuroimmune alterations following chronic opioid exposure that could be mediating maternal care deficits. This work provides a foundation to explore the extent to which modulation of neuroimmune activation may be a potential intervention for deficits in mothers exposed to opioids during pregnancy.

Genetic and neurochemical profiles underlying cortical morphometric vulnerability to Parkinson's disease.

Increasing evidence has documented cortical involvement at all stages of PD. The local vulnerabilities within certain brain regions in PD have been previously demonstrated, whereas its underlying genetic and neurochemical factors remain unclear. This study aims to investigate the spatial spectrum of cortical atrophy in Parkinson's disease (PD) and link these variances in gray matter properties and curvature respectively to putative molecular pathways and neurotransmitter factors. We recruited 141 clinically diagnosed PD patients and 70 healthy controls. Cortical morphological abnormalities of PD were obtained by intergroup comparisons in gray matter properties metrics and curvature measurements. Then we performed gene-category enrichment and spatial correlation analyses to evaluate the specific correspondence between cortical alteration in PD and genetic expression from the Allen Human Brain Atlas and normative neurotransmitter atlases from Neuromaps. We found decreased gray matter properties in temporal, somatomotor, cingulate and occipital cortices, decreased curvature measures in occipital, temporal and orbitofrontal cortices, and increased curvature measures in somatomotor, prefrontal and posterior parietal cortices for PD patients. The related genes were enriched for the glucose metabolism, mitochondrial function, and post-translational histone modifications processes. In addition, the serotonin and norepinephrine transporter devoted more to gray matter properties alterations while the dopamine, gamma-aminobutyric acid receptors, and norepinephrine transporter were strong contributors of curvature abnormalities in PD. Collectively, the present study offered interpretation of cortical morphological alterations and the cortical pathogenic theory in PD from genetic and neurochemical perspectives, which inspire further research on new pharmacotherapeutic approaches.

The polarity of high-definition transcranial direct current stimulation affects the planning and execution of movement sequences.

Noninvasive brain stimulation of the primary motor cortex has been shown to alter therapeutic outcomes in stroke and other neurological conditions, but the precise mechanisms remain poorly understood. Determining the impact of such neurostimulation on the neural processing supporting motor control is a critical step toward further harnessing its therapeutic potential in multiple neurological conditions affecting the motor system. Herein, we leverage the excellent spatio-temporal precision of magnetoencephalographic (MEG) imaging to identify the spectral, spatial, and temporal effects of high-definition transcranial direct current stimulation (HD-tDCS) on the neural responses supporting motor control. Participants (N = 67) completed three HD-tDCS visits (anode, cathode, sham), with each involving 20 minutes of left primary motor cortex stimulation and performance of a simple/complex motor sequencing task during MEG. Whole-brain statistical analyses of beta oscillatory responses revealed stimulation-by-task interaction effects in the left primary motor cortex, right occipitotemporal, and the right dorsolateral prefrontal cortices. Broadly, anodal stimulation induced significantly stronger beta oscillatory responses in these regions during simple movement sequences, while neural responses to complex sequences were not affected by stimulation. En masse, these data suggest that the beta oscillations serving motor planning (i.e., pre-movement) are particularly sensitive to the polarity of noninvasive stimulation and that the impact varies based on the difficulty of the movement sequence.

Cholinergic Denervation Patterns in Parkinson's Disease Associated With Cognitive Impairment Across Domains.

Cognitive impairment is considered to be one of the key features of Parkinson's disease (PD), ultimately resulting in PD-related dementia in approximately 80% of patients over the course of the disease. Several distinct cognitive syndromes of PD have been suggested, driven by different neurotransmitter deficiencies and thus requiring different treatment regimes. In this study, we aimed to identify characteristic brain covariance patterns that reveal how cholinergic denervation is related to PD and to cognitive impairment, focusing on four domains, including attention, executive functioning, memory, and visuospatial cognition. We applied scaled sub-profile model principal component analysis to reveal cholinergic-specific disease-related and cognition-related covariance patterns using [18F]fluoroethoxybenzovesamicol PET imaging. Stepwise logistic regression was applied to predict disease state (PD vs. healthy control). Linear regression models were applied to predict cognitive functioning within the PD group, for each cognitive domain separately. We assessed the performance of the identified patterns with leave-one-out cross validation and performed bootstrapping to assess pattern stability. We included 34 PD patients with various levels of cognitive dysfunction and 10 healthy controls, with similar age, sex, and educational level. The disease-related cholinergic pattern was strongly discriminative (AUC 0.91), and was most prominent in posterior brain regions, with lower tracer uptake in patients compared to controls. We found largely overlapping cholinergic-specific patterns across cognitive domains, with positive correlations between tracer uptake in the opercular cortex, left dorsolateral prefrontal cortex and posterior cingulate gyrus, among other regions, and attention, executive, and visuospatial functioning. Cross validation showed significant correlations between predicted and measured cognition scores, with the exception of memory. We identified a robust structural covariance pattern for the assessment of cholinergic dysfunction related to PD, as well as overlapping cholinergic patterns related to attentional, executive- and visuospatial impairment in PD patients.

Calcium-Binding Proteins in the Autistic Brain-Potential Links to Symptom Development.

Autism spectrum disorder (ASD) is a complex challenge, influenced by genetic and environmental factors. This review focuses on the proteins calbindin (CB), calretinin (CR) and parvalbumin (PV) in the context of ASD, exploring their clinical correlations and providing a deeper understanding of the spectrum. In addition, we seek to understand the role of these proteins in GABAergic regulation and their implication in the pathophysiology of ASD. The studies reviewed revealed a significant decrease in PV+ interneurons in the prefrontal cortex of individuals with ASD compared with typical controls. This reduction is associated with local synaptic hyperconnectivity, characterized by an increase in the number of excitatory synapses and a reduction in inhibitory synapses. A correlation was also observed between the decrease in PV+ and the severity of the behavioural symptoms of ASD. The research highlights GABAergic imbalance as a crucial component in the neuropathology of ASD, highlighting the role of calcium-binding proteins, especially PV, in regulating neuronal excitability and modulating synaptic connectivity. These findings provide valuable insights for the development of new therapeutic strategies intended to modulate neuronal activity and improve the symptoms associated with ASD.

Frontopolar Cortex Interacts With Dorsolateral Prefrontal Cortex to Causally Guide Metacognition.

Accurate metacognitive judgments about an individual's performance in a mental task require the brain to have access to representations of the quality and difficulty of first-order cognitive processes. However, little is known about how accurate metacognitive judgments are implemented in the brain. Here, we combine brain stimulation with functional neuroimaging to determine the neural and psychological mechanisms underlying the frontopolar cortex's (FPC) role in metacognition. Specifically, we evaluate two-layer neural architectures positing that FPC enables metacognitive judgments by communicating with brain regions encoding first-order decision difficulty. In support of two-layer architectures of metacognition, we found that high-intensity transcranial alternating current stimulation (tACS; 4 mA peak-to-peak) over FPC impaired metacognitive accuracy; at the neural level, this impairment was reflected by reduced coupling between FPC and dorsolateral prefrontal cortex (DLPFC), particularly during difficult metacognitive judgments. We also evaluated conceptual accounts assuming that metacognition relies on self-directed mentalizing. However, we observed no influence of FPC tACS on mentalizing performance and only a weak overlap of the networks underlying metacognition and mentalizing. Together, our findings put the FPC at the center of a two-layer architecture that enables accurate evaluations of cognitive processes, mainly via the FPC's connectivity with regions encoding first-level task difficulty, with little contributions from mentalizing-related processes.

Repetitive transcranial magnetic stimulation for fibromyalgia: are we there yet?

Repetitive transcranial magnetic stimulation (rTMS) has increasingly been used to modify cortical maladaptive plastic changes shown to occur in fibromyalgia (FM) and to correlate with symptoms. Evidence for its efficacy is currently inconclusive, mainly due to heterogeneity of stimulation parameters used in trials available to date. Here, we reviewed the current evidence on the use of rTMS for FM control in the format of a narrative review, in which a systematic dissection of the different stimulation parameters would be possible. We conducted a search in Medline and Embase for controlled trials on rTMS in people with FM with at least 10 participants in each treatment arm, and treatment/follow-up of at least 3 weeks. The search identified 482 abstracts, of which 45 were screened to full review, and 11 met inclusion criteria. Six out of 11 trials were positive. The dorsolateral prefrontal cortex was the target in 218 patients (49.2%), and the primary motor cortex (M1) in 225 (50.8%). Studies targeting M1 at 10 Hz, with stimulation current delivered in the posterior-anterior, were systematically positive, frequently showing that maintenance sessions delivered weekly, and biweekly were able to maintain the analgesic effects seen after daily induction sessions. Studies assessing the effects of rTMS for FM are still marked by heterogeneity in stimulation petameters, choice of primary outcomes, and inclusion criteria. The selection of the stimulation parameters associated with significant analgesic effects is likely to benefit following larger multicenter trials and improve the overall management of pain and associated symptoms in people with FM.

Chronic cannabis use differentially modulates neural oscillations serving the manipulate versus maintain components of working memory processing.

The legalization of recreational cannabis use has expanded the availability of this psychoactive substance in the United States. Research has shown that chronic cannabis use is associated with altered working memory function, however, the brain areas and neural dynamics underlying these affects remain poorly understood. In this study, we leveraged magnetoencephalography (MEG) to investigate neurophysiological activity in 45 participants (22 heavy cannabis users) during a numerical WM task, whereby participants were asked to either maintain or manipulate (i.e., rearrange in ascending order) a group of visually presented numbers. Significant oscillatory responses were imaged using a beamformer and subjected to whole-brain ANOVAs. Notably, we found that cannabis users exhibited significantly weaker alpha oscillations in superior parietal, occipital, and other regions during the encoding phase relative to nonusers. Interestingly, during the maintenance phase, there was a group-by-condition interaction in the right inferior frontal gyrus, left prefrontal, parietal, and other regions, such that cannabis users exhibited weaker alpha and beta oscillations relative to nonusers during maintain trials. Additionally, chronic cannabis users exhibited stronger alpha and beta maintenance responses in these same brain regions and prolonged reaction times during manipulate relative to maintain trials, while no such differences were found in nonusers. Neurobehavioral relationships were also detected in the prefrontal cortices of nonusers, but not cannabis users. In sum, chronic cannabis users exhibit weaker neural oscillations during working memory encoding but may compensate for these deficiencies through stronger oscillatory responses during memory maintenance, especially during strenuous tasks such as manipulating the to-be remembered items.