Functional brain connectivity changes associated with day-to-day fluctuations in affective states.

Affective neuroscience has traditionally relied on cross-sectional studies to uncover the brain correlates of affects, emotions, and moods. Such findings obfuscate intraindividual variability that may reveal meaningful changing affect states. The few functional magnetic resonance imaging longitudinal studies that have linked changes in brain function to the ebbs and flows of affective states over time have mostly investigated a single individual. In this study, we explored how the functional connectivity of brain areas associated with affective processes can explain within-person fluctuations in self-reported positive and negative affects across several subjects. To do so, we leveraged the Day2day dataset that includes 40 to 50 resting-state functional magnetic resonance imaging scans along self-reported positive and negative affectivity from a sample of six healthy participants. Sparse multivariate mixed-effect linear models could explain 15% and 11% of the within-person variation in positive and negative affective states, respectively. Evaluation of these models' generalizability to new data demonstrated the ability to predict approximately 5% and 2% of positive and negative affect variation. The functional connectivity of limbic areas, such as the amygdala, hippocampus, and insula, appeared most important to explain the temporal dynamics of affects over days, weeks, and months.

Aging disrupts locus coeruleus-driven norepinephrine transmission in the prefrontal cortex: Implications for cognitive and motor decline.

The locus coeruleus (LC)-prefrontal cortex (PFC) circuitry is crucial for cognition, planning, posture and mobility. This study examines the role of norepinephrine (NE) in elucidating the neurobiological basis of age-related cognitive and motor declines. Aged mice exhibited reduced spatial learning, impaired memory, decreased physical endurance, and notable changes in locomotor behavior. The neurochemical foundations of these deficits were investigated through fast-scan cyclic voltammetry to measure NE release in the PFC and LC, both in vivo and in brain slices. Additionally, oxygen levels were monitored as a proxy for PFC neuronal function, and NE levels were analyzed in the extracellular space via microdialysis and total content in the PFC. Aged mice exhibited a frequency-dependent increase in NE release in the PFC upon LC stimulation, suggesting alterations in neural responsiveness due to aging. We also recorded slower NE reuptake rates and increased NE content and neuronal activity, indicated by higher oxygen levels and facilitated neuron activation due to membrane depolarization recorded via whole-cell patch-clamp. To understand the basis for LC-driven NE surges in the PFC with aging, we examined the expression levels of two proteins critical for presynaptic NE release and NE reuptake: the α2a-adrenergic receptor and the NE transporter. Both showed a significant decrease in the PFC with aging. These findings support the concept that aging significantly alters the structural and functional dynamics within the LC-PFC neural circuit, impacting NE modulation and neuronal activity, which may underlie the observed declines in cognitive and motor functions in aging populations.

8-weeks aerobic exercise ameliorates cognitive deficit and mitigates ferroptosis triggered by iron overload in the prefrontal cortex of APP Swe/PSEN 1dE9 mice through Xc-/GPx4 pathway.

Background: Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of APP Swe/PSEN 1dE9 (APP/PS1) mice. Methods: Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, iron-metabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice. Results: In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc-/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice. Conclusion: 8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc- pathway in PFC to reduce ferroptosis induced by AD.

Repetition dynamically and rapidly increases cortical, but not hippocampal, offline reactivation.

No sooner is an experience over than its neural representation begins to be transformed through memory reactivation during offline periods. The lion's share of prior research has focused on understanding offline reactivation within the hippocampus. However, it is hypothesized that consolidation processes involve offline reactivation in cortical regions as well as coordinated reactivation in the hippocampus and cortex. Using fMRI, we presented novel and repeated paired associates to participants during encoding and measured offline memory reactivation for those events during an immediate post-encoding rest period. post-encoding reactivation frequency of repeated and once-presented events did not differ in the hippocampus. However, offline reactivation in widespread cortical regions and hippocampal-cortical coordinated reactivation were significantly enhanced for repeated events. These results provide evidence that repetition might facilitate the distribution of memory representations across cortical networks, a hallmark of systems-level consolidation. Interestingly, we found that offline reactivation frequency in both hippocampus and cortex explained variance in behavioral success on an immediate associative recognition test for the once-presented information, potentially indicating a role of offline reactivation in maintaining these novel, weaker, memories. Together, our findings highlight that endogenous offline reactivation can be robustly and significantly modulated by study repetition.

Representing the dynamics of natural marmoset vocal behaviors in frontal cortex.

Here, we tested the respective contributions of primate premotor and prefrontal cortex to support vocal behavior. We applied a model-based generalized linear model (GLM) analysis that better accounts for the inherent variance in natural, continuous behaviors to characterize the activity of neurons throughout the frontal cortex as freely moving marmosets engaged in conversational exchanges. While analyses revealed functional clusters of neural activity related to the different processes involved in the vocal behavior, these clusters did not map to subfields of prefrontal or premotor cortex, as has been observed in more conventional task-based paradigms. Our results suggest a distributed functional organization for the myriad neural mechanisms underlying natural social interactions and have implications for our concepts of the role that frontal cortex plays in governing ethological behaviors in primates.

Gender Differences in Prefrontal Cortex Response to Negative Emotional Stimuli in Drivers.

BACKGROUND: Road safety improvement is a governmental priority due to driver-caused accidents. Driving style variation affects safety, with emotional regulation being pivotal. However, functional near-infrared spectroscopy (fNIRS) studies show inconsistent prefrontal cortex activity during emotion processing. This study examines prefrontal cortex response to negative emotional stimuli, particularly traffic accident images, across drivers diverse in age and gender. METHOD: The study involved 118 healthy males (44.38 ± 12.98 years) and 84 females (38.89 ± 10.60 years). The Multidimensional Driving Style Inventory (MDSI) was used to assess driving behavior alongside fNIRS recordings. Participants viewed traffic accident and neutral images while prefrontal oxygenation was monitored. RESULTS: Women rated traffic accidents (t-test = 2.43; p < 0.016) and neutral images (t-test = 2.19; p < 0.030) lower in valence than men. Arousal differences were significant for traffic accident images (t-test = -3.06; p < 0.002). correlational analysis found an inverse relationship between Dissociative scale scores and oxygenation (all p-values ≤ 0.013). Greater prefrontal oxygenation occurred with neutral images compared to traffic accidents. Left hemisphere differences (t-test = 3.23; p < 0.001) exceeded right hemisphere differences (t-test = 2.46; p < 0.015). Subgroup analysis showed male participants to be driving these disparities. Among adaptive drivers, significant oxygenation differences between neutral and accident images were evident in both hemispheres (left: t-test = 2.72, p < 0.009; right: t-test = 2.22, p < 0.030). CONCLUSIONS: Male drivers with maladaptive driving styles, particularly dissociative ones, exhibit reduced prefrontal oxygenation when exposed to neutral and traffic accident images. This response was absent in female drivers, with no notable age-related differences.

Monoaminergic Modulation of Learning and Cognitive Function in the Prefrontal Cortex.

Extensive research has shed light on the cellular and functional underpinnings of higher cognition as influenced by the prefrontal cortex. Neurotransmitters act as key regulatory molecules within the PFC to assist with synchronizing cognitive state and arousal levels. The monoamine family of neurotransmitters, including dopamine, serotonin, and norepinephrine, play multifaceted roles in the cognitive processes behind learning and memory. The present review explores the organization and signaling patterns of monoamines within the PFC, as well as elucidates the numerous roles played by monoamines in learning and higher cognitive function.

The Role of the Mu Opioid Receptors of the Medial Prefrontal Cortex in the Modulation of Analgesia Induced by Acute Restraint Stress in Male Mice.

Mu opioid receptors (MORs) represent a vital mechanism related to the modulation of stress-induced analgesia (SIA). Previous studies have reported on the gamma-aminobutyric acid (GABA)ergic "disinhibition" mechanisms of MORs on the descending pain modulatory pathway of SIA induced in the midbrain. However, the role of the MORs expressed in the medial prefrontal cortex (mPFC), one of the main cortical areas participating in pain modulation, in SIA remains completely unknown. In this study, we investigated the contributions of MORs expressed on glutamatergic (MORGlut) and GABAergic (MORGABA) neurons of the medial prefrontal cortex (mPFC), as well as the functional role and activity of neurons projecting from the mPFC to the periaqueductal gray (PAG) region, in male mice. We achieved this through a combination of hot-plate tests, c-fos staining, and 1 h acute restraint stress exposure tests. The results showed that our acute restraint stress protocol produced mPFC MOR-dependent SIA effects. In particular, MORGABA was found to play a major role in modulating the effects of SIA, whereas MORGlut seemed to be unconnected to the process. We also found that mPFC-PAG projections were efficiently activated and played key roles in the effects of SIA, and their activation was mediated by MORGABA to a large extent. These results indicated that the activation of mPFC MORGABA due to restraint stress was able to activate mPFC-PAG projections in a potential "disinhibition" pathway that produced analgesic effects. These findings provide a potential theoretical basis for pain treatment or drug screening targeting the mPFC.

Circadian Rhythms in Conditioned Threat Extinction Reflect Time-of-Day Differences in Ventromedial Prefrontal Cortex Neural Processing.

Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction.

MeCP2 Deficiency Alters the Response Selectivity of Prefrontal Cortical Neurons to Different Social Stimuli.

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MeCP2 gene, is characterized by cognitive and social deficits. Previous studies have noted hypoactivity in the medial prefrontal cortex (mPFC) pyramidal neurons of MeCP2-deficient mice (RTT mice) in response to both social and nonsocial stimuli. To further understand the neural mechanisms behind the social deficits of RTT mice, we monitored excitatory pyramidal neurons in the prelimbic region of the mPFC during social interactions in mice. These neurons' activity was closely linked to social preference, especially in wild-type mice. However, RTT mice showed reduced social interest and corresponding hypoactivity in these neurons, indicating that impaired mPFC activity contributes to their social deficits. We identified six mPFC neural ensembles selectively tuned to various stimuli, with RTT mice recruiting fewer neurons to ensembles responsive to social interactions and consistently showing lower stimulus-ON ensemble transient rates. Despite these lower rates, RTT mice exhibited an increase in the percentage of social-ON neurons in later sessions, suggesting a compensatory mechanism for the decreased firing rate. This highlights the limited plasticity in the mPFC caused by MeCP2 deficiency and offers insights into the neural dynamics of social encoding. The presence of multifunctional neurons and those specifically responsive to social or object stimuli in the mPFC emphasizes its crucial role in complex behaviors and cognitive functions, with selective neuron engagement suggesting efficiency in neural activation that optimizes responses to environmental stimuli.

Psychopathy and medial frontal cortex: A systematic review reveals predominantly null relationships.

Theories have posited that psychopathy is caused by dysfunction in the medial frontal cortex, including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and dorsomedial prefrontal cortex (dmPFC). Recent reviews have questioned the reproducibility of neuroimaging findings within this field. We conducted a systematic review to describe the consistency of magnetic resonance imaging (MRI) findings according to anatomical subregion (vmPFC, ACC, dmPFC), experimental task, psychopathy assessment, study power, and peak coordinates of significant effects. Searches of PsycInfo and MEDLINE databases produced 77 functional and 24 structural MRI studies that analyzed the medial frontal cortex in relation to psychopathy in adult samples. Findings were predominantly null (85.4% of 1,573 tests across the three medial frontal regions). Studies with higher power observed null effects at marginally lower rates. Finally, peak coordinates of significant effects were widely dispersed. The evidence failed to support theories positing the medial frontal cortex as a consistent neural correlate of psychopathy. Theory and methods in the field should be revised to account for predominantly null neuroimaging findings.

Third-party punishment-like behavior in a rat model.

Third-party punishment (TPP) is an altruistic behavior or sense willing to punish transgressors as a third party not directly involved in the transgression. TPP is observed worldwide, regardless of tradition and culture, and is essential for morality in human society. Moreover, even preverbal infants display TPP-like judgement, suggesting that TPP is evolutionarily conserved and innate. Thus, it is possible that non-human animals display TPP-like behavior, although TPP has been said to be human-specific. We investigated whether or not male mature Wistar rats displayed TPP-like behaviors when they witnessed deadly aggression by an unknown aggressive mouse toward another unknown victim mouse. Normally reared rats did not display TPP-like behaviors, but rats reared with extensive affectionate handling by human caretakers as beloved pets contacted the unknown aggressive mice in a gentle manner leading to reduced aggression toward the unknown victim mice, even when the aggressive mice fought back. Furthermore, the handled rats touched unknown rat pups that were drowning in water and anesthesia-induced comatose rats more frequently than control rats. These findings suggest a possibility that TPP is not in fact human-specific and innate but rather an acquired behavior that flourishes in affectionate circumstances.

Higher levels of AKT-interacting protein in the frontal pole from people with schizophrenia are limited to a sub-group who have a marked deficit in cortical muscarinic M1 receptors.

We are studying the molecular pathology of a sub-group within schizophrenia (∼ 25 %: termed Muscarinic Receptor Deficit subgroup of Schizophrenia (MRDS)) who can be separated because they have very low levels of cortical muscarinic M1 receptors (CHRM1). Based on our transcriptomic data from Brodmann's area ((BA) 9, 10 and 33 (controls, schizophrenia and mood disorders) and the cortex of the CHRM1-/- mouse (a molecular model of aberrant CHRM1 signaling), we predicted levels of AKT interacting protein (AKTIP), but not tubulin alpha 1b (TUBA1B) or AKT serine/threonine kinase 1 (AKT1) and pyruvate dehydrogenase kinase 1 (PDK1) (two AKTIP-functionally associated proteins), would be changed in MRDS. Hence, we used Western blotting to measure AKTIP (BA 10: controls, schizophrenia and mood disorders; BA 9: controls and schizophrenia) plus TUBA1B, AKT1 and PDK1 (BA 10: controls and schizophrenia) proteins. The only significant change with diagnosis was higher levels of AKTIP protein in BA 10 (Cohen's d = 0.73; p = 0.02) in schizophrenia compared to controls due to higher levels of AKTIP only in people with MRDS (Cohen's d = 0.80; p = 0.03). As AKTIP is involved in AKT1 signaling, our data suggests that signaling pathway is particularly disturbed in BA 10 in MRDS.

Prefrontal Metabolite Alterations in Individuals with Posttraumatic Stress Disorder: A 7T Magnetic Resonance Spectroscopy Study.

Background: Evidence from animal and human studies suggests glutamatergic dysfunction in posttraumatic stress disorder (PTSD). The purpose of this study was to investigate glutamate abnormalities in the dorsolateral prefrontal cortex (DLFPC) of individuals with PTSD using 7T MRS, which has better spectral resolution and signal-to-noise ratio than lower field strengths, thus allowing for better spectral quality and higher sensitivity. We hypothesized that individuals with PTSD would have lower glutamate levels compared to trauma-exposed individuals without PTSD and individuals without trauma exposure. Additionally, we explored potential alterations in other neurometabolites and the relationship between glutamate and psychiatric symptoms. Methods: Individuals with PTSD (n = 27), trauma-exposed individuals without PTSD (n = 27), and individuals without trauma exposure (n = 26) underwent 7T MRS to measure glutamate and other neurometabolites in the left DLPFC. The severities of PTSD, depression, anxiety, and dissociation symptoms were assessed. Results: We found that glutamate was lower in the PTSD and trauma-exposed groups compared to the group without trauma exposure. Furthermore, N-acetylaspartate (NAA) was lower and lactate was higher in the PTSD group compared to the group without trauma exposure. Glutamate was negatively correlated with depression symptom severity in the PTSD group. Glutamate was not correlated with PTSD symptom severity. Conclusion: In this first 7T MRS study of PTSD, we observed altered concentrations of glutamate, NAA, and lactate. Our findings provide evidence for multiple possible pathological processes in individuals with PTSD. High-field MRS offers insight into the neurometabolic alterations associated with PTSD and is a powerful tool to probe trauma- and stress-related neurotransmission and metabolism in vivo.

The ventromedial prefrontal cortex plays an important role in implicit emotion regulation: A focality-optimized multichannel tDCS study in anxiety individuals.

The regulation of emotions is a crucial facet of well-being and social adaptability, with explicit strategies receiving primary attention in prior research. Recent studies, however, emphasize the role of implicit emotion regulation, particularly implicating the ventromedial prefrontal cortex (VMPFC) in association with its implementation. This study delves into the nuanced role of the VMPFC through focality-optimized multichannel transcranial direct current stimulation (tDCS), shedding light on its causal involvement in implicit reappraisal. The primary goal was to evaluate the effectiveness of VMFPC-targeted tDCS and elucidate its role in individuals with high trait anxiety. Participants engaged in implicit and explicit emotion regulation tasks during multichannel tDCS targeting the VMPFC. The outcome measures encompassed negative emotion ratings, pupillary diameter, and saccade count, providing a comprehensive evaluation of emotion regulation efficiency. The intervention exhibited a notable impact, resulting in significant reductions in negative emotion ratings and pupillary reactions during implicit reappraisal, highlighting the indispensable role of the VMPFC in modulating emotional responses. Notably, these effects demonstrated sustained efficacy up to 1 day postintervention. This study underscores the potency of VMPFC-targeted multichannel tDCS in augmenting implicit emotion regulation. This not only contributes insights into the neural mechanisms of emotion regulation but also suggests innovative therapeutic avenues for anxiety disorders. The findings present a promising trajectory for future mood disorder interventions, bridging the gap between implicit emotion regulation and neural stimulation techniques.

Quantifying network behavior in the rat prefrontal cortex.

The question of how consciousness and behavior arise from neural activity is fundamental to understanding the brain, and to improving the diagnosis and treatment of neurological and psychiatric disorders. There is significant murine and primate literature on how behavior is related to the electrophysiological activity of the medial prefrontal cortex and its role in working memory processes such as planning and decision-making. Existing experimental designs, specifically the rodent spike train and local field potential recordings during the T-maze alternation task, have insufficient statistical power to unravel the complex processes of the prefrontal cortex. We therefore examined the theoretical limitations of such experiments, providing concrete guidelines for robust and reproducible science. To approach these theoretical limits, we applied dynamic time warping and associated statistical tests to data from neuron spike trains and local field potentials. The goal was to quantify neural network synchronicity and the correlation of neuroelectrophysiology with rat behavior. The results show the statistical limitations of existing data, and the fact that making meaningful comparison between dynamic time warping with traditional Fourier and wavelet analysis is impossible until larger and cleaner datasets are available.

Changes in the medial prefrontal cortex metabolites after 6 months of medication therapy for patients with bipolar disorder: A 1H-MRS study.

AIMS: The study aimed to assess brain metabolite differences in the medial prefrontal cortex (mPFC) between acute and euthymic episodes of bipolar disorder (BD) with both mania and depression over a 6-month medication treatment period. METHODS: We utilized 1H-MRS technology to assess the metabolite levels in 53 individuals with BD (32 in depressive phase, 21 in manic phase) and 34 healthy controls (HCs) at baseline. After 6 months of medication treatment, 40 subjects underwent a follow-up scan in euthymic state. Metabolite levels, including N-acetyl aspartate (NAA), glutamate (Glu), and Glutamine (Gln), were measured in the mPFC. RESULTS: Patients experiencing depressive and manic episodes exhibited a notable reduction in NAA/Cr + PCr ratios at baseline compared to healthy controls (p = 0.004; p = 0.006) in baseline, compared with HCs. Over the 6-month follow-up period, the manic group displayed a significant decrease in Gln/Cr + PCr compared to the initial acute phase (p = 0.03). No significant alterations were found in depressed group between baseline and follow-up. CONCLUSION: This study suggests that NAA/Cr + PCr ratios and Gln/Cr + PCr ratios in the mPFC may be associated with manic and depressive episodes, implicating that Gln and NAA might be useful biomarkers for distinguishing mood phases in BD and elucidating its mechanisms.

Characterization of neural networks involved in transdiagnostic emotion dysregulation from a pilot randomized controlled trial of a neurostimulation-enhanced behavioral intervention.

BACKGROUND: Emotional dysregulation is a serious and impairing mental health problem. We examined functional activity and connectivity of neural networks involved in emotional dysregulation at baseline and following a pilot neurostimulation-enhanced cognitive restructuring intervention in a transdiagnostic clinical adult sample. METHODS: Neuroimaging data were analyzed from adults who scored 89 or higher on the Difficulties with Emotion Regulation (DERS) scale and had at least one DSM-5 diagnosis. These participants were part of a pilot randomized, double-blind, placebo-controlled trial combining a single therapeutic session of cognitive restructuring with active or sham transcranial magnetic stimulation over the dorsolateral prefrontal cortex. During the study, participants engaged in an emotional regulation task using personalized autobiographical stressors while undergoing functional magnetic resonance imaging (fMRI) before and after the pilot intervention. The fMRI task required participants to either experience the emotions associated with the memories or apply cognitive restructuring strategies to reduce their distress. RESULTS: Whole-brain fMRI results during regulation at baseline revealed increased activation in the dorsal frontoparietal network but decreased activation in the supplementary motor area, cingulate cortex, insula, and ventrolateral prefrontal cortex (vlPFC). Emotion dysregulation was associated with greater vmPFC and amygdala activation and functional connectivity between these regions. The strength of functional connectivity between the dlPFC and other frontal regions was also a marker of emotional dysregulation. Preliminary findings from a subset of participants who completed the follow-up fMRI scan showed that active neurostimulation improved behavioral indices of emotion regulation more than sham stimulation. A whole-brain generalized psychophysiological interaction analysis indicated that active neurostimulation selectively increased occipital cortex connectivity with both the insula and the dlPFC. Region-of-interest functional connectivity analyses showed that active neurostimulation selectively increased dlPFC connectivity with the insula and orbitofrontal cortex (OFC). CONCLUSION: Insufficient neural specificity during the emotion regulation process and over-involvement of frontal regions may be a marker of emotional dysregulation across disorders. OFC, vlPFC, insula activity, and connectivity are associated with improved emotion regulation in transdiagnostic adults. In this pilot study, active neurostimulation led to neural changes in the emotion regulation network after a single session; however, the intervention findings are preliminary, given the small sample size. These functional network properties can inform future neuroscience-driven interventions and larger-scale studies.

Disturbances of thalamus and prefrontal cortex contribute to cognitive aging: A structure-function coupling analysis based on KL divergence.

Normal aging is accompanied by changes in brain structure and function associated with cognitive decline. Structural and functional abnormalities, particularly the prefrontal cortex (PFC) and subcortical regions, contributed to cognitive aging. However, it remains unclear how the synchronized changes in structure and function of individual brain regions affect the cognition in aging. Using 3D T1-weighted structural data and movie watching functional magnetic resonance imaging data in a sample of 422 healthy individuals (ages from 18 to 87 years), we constructed regional structure-function coupling (SFC) of cortical and subcortical regions by quantifying the distribution similarity of gray matter volume (GMV) and amplitude of low-frequency fluctuation (ALFF). Further, we investigated age-related changes in SFC and its relationship with cognition. With aging, increased SFC localized in PFC, thalamus and caudate nucleus, decreased SFC in temporal cortex, lateral occipital cortex and putamen. Moreover, the SFC in the PFC was associated with executive function and thalamus was associated with the fluid intelligence, and partially mediated age-related cognitive decline. Collectively, our results highlight that tighter structure-function synchron of the PFC and thalamus might contribute to age-related cognitive decline, and provide insight into the substrate of the thalamo-prefrontal pathway with cognitive aging.

Repeated prefrontal tDCS for improving mental health and cognitive deficits in multiple sclerosis: a randomized, double-blind, parallel-group study.

BACKGROUND: Multiple Sclerosis (MS) is an autoimmune disease associated with physical disability, psychological impairment, and cognitive dysfunctions. Consequently, the disease burden is substantial, and treatment choices are limited. In this randomized, double-blind study, we conducted repeated prefrontal electrical stimulation in 40 patients with MS to evaluate mental health variables (quality of life, sleep difficulties, psychological distress) and cognitive dysfunctions (psychomotor speed, working memory, attention/vigilance), marking it as the third largest sample size tDCS research conducted in MS to date. METHODS: The patients were randomly assigned (block randomization method) to two groups of sham (n = 20), or 1.5-mA (n = 20) transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (F3) and right frontopolar cortex (Fp2) with anodal and cathodal stimulation respectively (electrode size: 25 cm2). The treatment included 10 sessions of 20 min of stimulation delivered every other day. Outcome measures were MS quality of life, sleep quality, psychological distress, and performance on a neuropsychological test battery dedicated to cognitive dysfunctions in MS (psychomotor speed, working memory, and attention). All outcome measures were evaluated at the pre-intervention and post-intervention assessments. Both patients and technicians delivering the stimulation were unaware of the type of stimulation being used. RESULTS: Repeated prefrontal real tDCS significantly improved quality of life and reduced sleep difficulties and psychological distress compared to the sham group. It, furthermore, improved psychomotor speed, attention, and vigilance compared to the sham protocol. Improvement in mental health outcome variables and cognitive outperformance were interrelated and could predict each other. CONCLUSIONS: Repeated prefrontal and frontopolar tDCS ameliorates secondary clinical symptoms related to mental health and results in beneficial cognitive effects in patients with MS. These results support applying prefrontal tDCS in larger trials for improving mental health and cognitive dysfunctions in MS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06401928.