Noninvasive brain stimulations modulated brain modular interactions to ameliorate working memory in community-dwelling older adults.

Non-invasive brain stimulations have drawn attention in remediating memory decline in older adults. However, it remains unclear regarding the cognitive and neural mechanisms underpinning the neurostimulation effects on memory rehabilitation. We evaluated the intervention effects of 2-weeks of neurostimulations (high-definition transcranial direct current stimulation, HD-tDCS, and electroacupuncture, EA versus controls, CN) on brain activities and functional connectivity during a working memory task in normally cognitive older adults (age 60+, n = 60). Results showed that HD-tDCS and EA significantly improved the cognitive performance, potentiated the brain activities of overlapping neural substrates (i.e. hippocampus, dlPFC, and lingual gyrus) associated with explicit and implicit memory, and modulated the nodal topological properties and brain modular interactions manifesting as increased intramodular connection of the limbic-system dominated network, decreased intramodular connection of default-mode-like network, as well as stronger intermodular connection between frontal-dominated network and limbic-system-dominated network. Predictive model further identified the neuro-behavioral association between modular connections and working memory. This preliminary study provides evidence that noninvasive neurostimulations can improve older adults' working memory through potentiating the brain activity of working memory-related areas and mediating the modular interactions of related brain networks. These findings have important implication for remediating older adults' working memory and cognitive declines.

Systemic lupus erythematosus-related brain abnormalities in the default mode network and the limbic system: A resting-state fMRI meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an immune-mediated and multi-systemic disease which may affect the nervous system, causing neuropsychiatric SLE (NPSLE). Recent neuroimaging studies have examined brain functional alterations in SLE. However, discrepant findings were reported. This meta-analysis aims to identify consistent resting-state functional abnormalities in SLE. METHODS: PubMed and Web of Science were searched to identify candidate resting-state functional MRI studies assessing SLE. A voxel-based meta-analysis was performed using the anisotropic effect-size version of the seed-based d mapping (AES-SDM). The abnormal intrinsic functional patterns extracted from SDM were mapped onto the brain functional network atlas to determine brain abnormalities at a network level. RESULTS: Twelve studies evaluating fifteen datasets were included in this meta-analysis, comprising 572 SLE patients and 436 healthy controls (HCs). Compared with HCs, SLE patients showed increased brain activity in the bilateral hippocampus and right superior temporal gyrus, and decreased brain activity in the left superior frontal gyrus, left middle temporal gyrus, bilateral thalamus, left inferior frontal gyrus and right cerebellum. Mapping the abnormal patterns to the network atlas revealed the default mode network and the limbic system as core neural systems commonly affected in SLE. LIMITATIONS: The number of included studies is relatively small, with heterogeneous analytic methods and a risk of publication bias. CONCLUSIONS: Brain functional alterations in SLE are predominantly found in the default mode network and the limbic system. These findings uncovered a consistent pattern of resting-state functional network abnormalities in SLE which may serve as a potential objective neuroimaging biomarker.

Altered functional-structural coupling may predict Parkinson's patient's depression.

We aimed to elucidate the neurobiological basis of depression in Parkinson's disease and identify potential imaging markers for depression in patients with Parkinson's disease. We recruited 43 normal controls (NC), 46 depressed Parkinson's disease patients (DPD) and 56 non-depressed Parkinson's disease (NDPD). All participants underwent routine T2-weighted, T2Flair, and resting-state scans on the same 3.0 T magnetic resonance imaging (MRI) scanner at our hospital. Pre-processing includes calculating surface-based Regional Homogeneity (2DReHo) and cortical thickness. Then we defined the correlation coefficient between 2DReHo and cortical thickness as the functional-structural coupling index. Between-group comparisons were conducted on the Fisher's Z-transformed correlation coefficients. To identify specific regions of decoupling, the 2DReHo for each participant were divided by cortical thickness at each vertex, followed by threshold-free cluster enhancement (TFCE) multiple comparison correction. Binary logistic regression analysis was performed with DPD as the dependent variable, and significantly altered indicators as the independent variables. Receiver operating characteristic curves were constructed to compare the diagnostic performance of individual predictors and combinations using R and MedCalc software. DPD patients exhibited a significantly lower whole-brain functional-structural coupling index than NDPD patients and NC. Abnormal functional-structural coupling was primarily observed in the left inferior parietal lobule and right primary and early visual cortices in DPD patients. Receiver operating characteristic analysis revealed that the combination of cortical functional-structural coupling, surface-based ReHo, and thickness had the best diagnostic performance, achieving a sensitivity of 65% and specificity of 77.7%. This is the first study to explore the relationship between functional and structural changes in DPD patients and evaluate the diagnostic performance of these altered correlations to predict depression in Parkinson's disease patients. We posit that these changes in functional-structural relationships may serve as imaging biomarkers for depression in Parkinson's disease patients, potentially aiding in the classification and diagnosis of Parkinson's disease. Additionally, our findings provide functional and structural imaging evidence for exploring the neurobiological basis of depression in Parkinson's disease.

The role of posterior parietal cortex in detecting changes in feedback contingency.

Well-practiced or learned behaviors are extremely resilient. For example, it is extremely difficult for a trained typist to forget how to use a keyboard configuration that they are familiar with. While they can be trained on a new keyboard configuration, the original skill quickly comes back when the old keyboard configuration is used again. This resiliency of learned skills is both a blessing and a curse. It makes useful skills durable, but it also makes maladaptive behaviors difficult to extinguish. Crossley et al. (2013) proposed a computational model and behavioral paradigm aimed at unlearning skills using various feedback contingency manipulations during an extinction phase. They showed that partially-valid feedback during extinction removed evidence for fast reacquisition, which they interpreted as evidence for unlearning. In this article, we replicated the Crossley et al. paradigm using fMRI. Univariate analyses showed differences in BOLD signals between the different experiment phases in the frontoparietal attention network. The superior and inferior parietal lobules (SPL and IPL, respectively) showed the largest cluster differences both between experimental phases and between extinction conditions. In contrast, the prefrontal cortex only showed differences in cluster of activities between extinction conditions. Multivariate pattern analysis was also used with seeds in the SPL and IPL. The results showed that these brain areas were critical in detecting changes in experimental phases. Overall, the fMRI results found mixed evidence for the Crossley et al. model and suggest that while unlearning prevents fast reacquisition, the absence of fast reacquisition does not necessarily implies that unlearning occurred.

What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.

The difference in volumetric alternations of the orbitofrontal-limbic-striatal system between major depressive disorder and anxiety disorders: A systematic review and voxel-based meta-analysis.

BACKGROUND: Major depressive disorder (MDD) and anxiety disorders (ANX) are psychiatric disorders with high mutual comorbidity rates that might indicate some shared neurobiological pathways between them, but they retain diverse phenotypes that characterize themselves specifically. However, no consistent evidence exists for common and disorder-specific gray matter volume (GMV) alternations between them. METHODS: A systematic review and meta-analysis on voxel-based morphometry studies of patients with MDD and ANX were performed. The effect of comorbidity was explicitly controlled during disorder-specific analysis and particularly investigated in patient with comorbidity. RESULTS: A total of 45 studies with 54 datasets comprising 2196 patients and 2055 healthy participants met the inclusion criteria. Deficits in the orbitofrontal cortex, striatum, and limbic regions were found in MDD and ANX. The disorder-specific analyses showed decreased GMV in the bilateral anterior cingulate cortex, right striatum, hippocampus, and cerebellum in MDD, while decreased GMV in the left striatum, amygdala, insula, and increased cerebellar volume in ANX. A totally different GMV alternation pattern was shown involving bilateral temporal and parietal gyri and left fusiform gyrus in patients with comorbidity. LIMITATIONS: Owing to the design of included studies, only partial patients in the comorbid group had a secondary comorbidity diagnosis. CONCLUSION: Patients with MDD and ANX shared a structural disruption in the orbitofrontal-limbic-striatal system. The disorder-specific effects manifested their greatest severity in distinct lateralization and directionality of these changes that differentiate MDD from ANX. The comorbid group showed a totally different GMV alternation pattern, possibly suggesting another illness subtype that requires further investigation.

From active affordance to active inference: vertical integration of cognition in the cerebral cortex through dual subcortical control systems.

In previous papers, we proposed that the dorsal attention system's top-down control is regulated by the dorsal division of the limbic system, providing a feedforward or impulsive form of control generating expectancies during active inference. In contrast, we proposed that the ventral attention system is regulated by the ventral limbic division, regulating feedback constraints and error-correction for active inference within the neocortical hierarchy. Here, we propose that these forms of cognitive control reflect vertical integration of subcortical arousal control systems that evolved for specific forms of behavior control. The feedforward impetus to action is regulated by phasic arousal, mediated by lemnothalamic projections from the reticular activating system of the lower brainstem, and then elaborated by the hippocampus and dorsal limbic division. In contrast, feedback constraint-based on environmental requirements-is regulated by the tonic activation furnished by collothalamic projections from the midbrain arousal control centers, and then sustained and elaborated by the amygdala, basal ganglia, and ventral limbic division. In an evolutionary-developmental analysis, understanding these differing forms of active affordance-for arousal and motor control within the subcortical vertebrate neuraxis-may help explain the evolution of active inference regulating the cognition of expectancy and error-correction within the mammalian 6-layered neocortex.

Limbic system plasticity after electroacupuncture intervention in knee osteoarthritis rats.

Knee osteoarthritis (KOA) is characterized by debilitating pain. Electroacupuncture (EA), a traditional Chinese medical therapy, has shown promise in KOA pain management. This study investigated the therapeutic potential of EA in KOA and its impact on limbic system neural plasticity. Sixteen rats were randomly assigned into two groups: EA group and sham-EA group. EA or sham-EA interventions were administered at acupoints ST32 (Futu) and ST36 (Zusanli) for three weeks. Post-intervention resting-state fMRI was scanned, assessing parameters including Amplitude of low frequency fluctuations (ALFF), regional homogeneity (ReHo), functional connectivity (FC) and nodal characterizations of network within limbic system. The results showed that EA was strategically directed towards the limbic system, resulting in discernible alterations in neural activity, FC, and network characteristics. Our findings demonstrate that EA had a significant impact on the limbic system neural plasticity in rats with KOA, presenting a novel nonpharmacological approach for KOA treatment.

Binge-like ethanol exposure during the brain growth spurt disrupts the function of retrosplenial cortex-projecting anterior thalamic neurons in adolescent mice.

Ethanol (EtOH) exposure during late pregnancy leads to enduring impairments in learning and memory that may stem from damage to components of the posterior limbic memory system, including the retrosplenial cortex (RSC) and anterior thalamic nuclei (ATN). In rodents, binge-like EtOH exposure during the first week of life (equivalent to the third trimester of human pregnancy) triggers apoptosis in these brain regions. We hypothesized that this effect induces long-lasting alterations in the function of RSC-projecting ATN neurons. To test this hypothesis, vesicular GABA transporter-Venus mice (expressing fluorescently tagged GABAergic interneurons) were subjected to binge-like EtOH vapor exposure on postnatal day (P) 7. This paradigm activated caspase 3 in the anterodorsal (AD), anteroventral (AV), and reticular thalamic nuclei at P7 but did not reduce neuronal density in these areas at P60-70. At P40-60, we injected red retrobeads into the RSC and performed patch-clamp slice electrophysiological recordings from retrogradely labeled neurons in the AD and AV nuclei 3-4 days later. We found significant effects of treatment on instantaneous action potential (AP) frequency and AP overshoot, as well as sex × treatment interactions for AP threshold and overshoot in AD neurons. A sex × treatment interaction was detected for AP number in AV neurons. EtOH exposure also reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents and increased the charge transfer of spontaneous inhibitory postsynaptic currents. These results highlight a novel cellular mechanism that could contribute to the lasting learning and memory deficits associated with developmental EtOH exposure.

Associations between cortisol stress responses and limbic volume and thickness in young adults: An exploratory study.

The investigation of the relationship between neural measures of limbic structures and hypothalamic pituitary adrenal axis responses to acute stress exposure in healthy young adults has so far focused in particular on task-based and resting state functional connectivity studies. Thus, the present study examined the association between limbic volume and thickness measures and acute cortisol responses to the psychosocial stress paradigm ScanSTRESS. Using Permutation Analysis of Linear Models controlling for sex, age and total brain volume, the associations between (sex-specific) cortisol increases and human connectome project style anatomical variables of limbic structures (i.e. volume and thickness) were investigated in 66 healthy and young (18-33 years) subjects (35 men, 31 women taking oral contraceptives). In addition, exploratory (sex-specific) bivariate correlations between cortisol increases and structural measures were conducted. The present data provide interesting new insights into the involvement of striato-limbic structures in psychosocial stress processing, suggesting that acute cortisol stress responses are also associated with mere structural measures of the human brain. Thus, our preliminary findings suggest that not only situation- and context-dependent reactions of the limbic system (i.e. blood oxygenation level-dependent reactions) are related to acute (sex-specific) cortisol stress responses but also basal and somewhat more constant structural measures. Our study hereby paves the way for further analyses in this context and highlights the relevance of the topic.

Association between limbic system lesions and anxiety in persons with multiple sclerosis.

BACKGROUND: Persons with Multiple Sclerosis (PwMS) have a higher rate of anxiety and depression than the general population. Depression has been associated with clinical relapses; temporal lesions were shown to predict depression severity. Anxiety is considerably understudied. The role of MS lesions in the limbic system is also understudied, partly due to difficulties identifying limbic lesions on standard 1.5 and 3 Tesla MRI. METHODS: This is a retrospective study of 23 PwMS who underwent 7T MRI on the same day as completing the Hospital Anxiety and Depression Scale (HADS). MRI was performed on a Siemens 7T MRI Plus and an 8-channel transmit coil with 32 receiver channels operating in pTx mode. MP2RAGE and DIR-SPACE sequences were analyzed to determine the number of lesions within the limbic system. RESULTS: The median number of lesions in the limbic system was 2.0 (range 0-7). When comparing the presence or absence of lesions in the limbic system, there was a significant relationship with anxiety (X2 (1, N = 23)=4.44, p = 0.035), but not for depression. CONCLUSION: Although only a small sample size, this study provides preliminary evidence that lesions in the limbic system are associated with the presence of anxiety in PwMS. This relationship warrants further investigation.

Anatomical characterisation of three different psychosurgical targets in the subthalamic area: from the basal ganglia to the limbic system.

Effective neural stimulation for the treatment of severe psychiatric disorders needs accurate characterisation of surgical targets. This is especially true for the medial subthalamic region (MSR) which contains three targets: the anteromedial STN for obsessive compulsive disorder (OCD), the medial forebrain bundle (MFB) for depression and OCD, and the "Sano triangle" for pathological aggressiveness. Blocks containing the subthalamic area were obtained from two human brains. After obtaining 11.7-Tesla MRI, blocks were cut in regular sections for immunohistochemistry. Fluorescent in situ hybridisation was performed on the macaque MSR. Electron microscopic observation for synaptic specialisation was performed on human and macaque subthalamic fresh samples. Images of human brain sections were reconstructed in a cryoblock which was registered on the MRI and histological slices were then registered. The STN contains glutamatergic and fewer GABAergic neurons and has no strict boundary with the adjacent MSR. The anteromedial STN has abundant dopaminergic and serotoninergic innervation with very sparse dopaminergic neurons. The MFB is composed of dense anterior dopaminergic and posterior serotoninergic fibres, and fewer cholinergic and glutamatergic fibres. Medially, the Sano triangle presumably contains orexinergic terminals from the hypothalamus, and neurons with strong nuclear oestrogen receptor-alpha staining with a decreased anteroposterior and mediolateral gradient of staining. These findings provide new insight regarding MSR cells and their fibre specialisation, forming a transition zone between the basal ganglia and the limbic systems. Our 3D reconstruction enabled us to visualize the main histological features of the three targets which should enable better targeting and understanding of neuromodulatory stimulation results in severe psychiatric conditions.

Lateralization of the hippocampus: A review of molecular, functional, and physiological properties in health and disease.

The hippocampus is a part of the brain's medial temporal lobe that is located under the cortex. It belongs to the limbic system and helps to collect and transfer information from short-term to long-term memory, as well as spatial orientation in each mammalian brain hemisphere. After more than two centuries of research in brain asymmetry, the hippocampus has attracted much attention in the study of brain lateralization. The hippocampus is very important in cognitive disorders, related to seizures and dementia, such as epilepsy and Alzheimer's disease. In addition, the motivation to study the hippocampus has increased significantly due to the asymmetry in the activity of the left and right hippocampi in healthy people, and its disruption during some neurological diseases. After a general review of the hippocampal structure and its importance in related diseases, the asymmetry in the brain with a focus on the hippocampus during the growth and maturation of healthy people, as well as the differences created in patients at the molecular, functional, and physiological levels are discussed. Most previous work indicates that the hippocampus is lateralized in healthy people. Also, lateralization at different levels remarkably changes in patients, and it appears that the most complex cognitive disorder is caused by a new dominant asymmetric system.

Signatures of Electrical Stimulation Driven Network Interactions in the Human Limbic System.

Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomic, neurophysiological, and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In eight patients (four male, four female) with drug-resistant epilepsy, we stimulated the limbic system with single-pulse electrical stimulation. Reliable corticocortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the "limbic Hippocampus-Anterior nucleus of the thalamus-Posterior cingulate, HAP-wave." This limbic HAP-wave was visually distinct and separately decoded from the CCEP waveform in ACC after amygdala stimulation. Diffusion MRI data show that the measured end points in the PCC overlap with the end points of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic HAP-wave may travel through fornix, mammillary bodies, and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic HAP-wave but with an earlier latency. Limbic subsystems have unique stimulation-evoked signatures that may be used in the future to help network pathology diagnosis.SIGNIFICANCE STATEMENT The limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimer's disease, and characterizing its typical circuit responses may provide diagnostic insight. Stimulation-evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation-evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the "limbic HAP-wave." The limbic HAP-wave follows anatomic white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.

Neural dynamics in the limbic system during male social behaviors.

Sexual and aggressive behaviors are vital for species survival and individual reproductive success. Although many limbic regions have been found relevant to these behaviors, how social cues are represented across regions and how the network activity generates each behavior remains elusive. To answer these questions, we utilize multi-fiber photometry (MFP) to simultaneously record Ca2+ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic regions in male mice during mating and fighting. We find that conspecific sensory information and social action signals are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in the network functional connectivity during the social action initiation phase, whereas late copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.

Distributed attribute representation in the superior parietal lobe during probabilistic decision-making.

Several studies have examined the neural substrates of probabilistic decision-making, but few have systematically investigated the neural representations of the two objective attributes of probabilistic rewards, that is, the reward amount and the probability. Specifically, whether there are common or distinct neural activity patterns to represent the objective attributes and their association with the neural representation of the subjective valuation remains largely underexplored. We conducted two studies (nStudy1 = 34, nStudy2 = 41) to uncover distributed neural representations of the objective attributes and subjective value as well as their association with individual probability discounting rates. The amount and probability were independently manipulated to better capture brain signals sensitive to these two attributes and were presented simultaneously in Study 1 and successively in Study 2. Both univariate and multivariate pattern analyses showed that the brain activities in the superior parietal lobule (SPL), including the postcentral gyrus, were modulated by the amount of rewards and probability in both studies. Further, representational similarity analysis revealed a similar neural representation between these two objective attributes and between the attribute and valuation. Moreover, the SPL tracked the subjective value integrated by the hyperbolic function. Probability-related brain activations in the inferior parietal lobule were associated with the variability in individual discounting rates. These findings provide novel insights into a similar neural representation of the two attributes during probabilistic decision-making and perhaps support the common neural coding of stimulus objective properties and subjective value in the field of probabilistic discounting.

Multimodal quantitative magnetic resonance imaging of the thalamus in tinnitus patients with different outcomes after sound therapy.

AIMS: This study systematically investigated structural and functional alterations in the thalamus and its subregions using multimodal magnetic resonance imaging (MRI) and examined its clinical relevance in tinnitus patients with different outcomes after sound therapy (narrowband noise). METHODS: In total, 60 patients with persistent tinnitus and 57 healthy controls (HCs) were recruited. Based on treatment efficacy, 28 patients were categorized into the effective group and 32 into the ineffective group. Five MRI measurements of the thalamus and its seven subregions, including gray matter volume, fractional anisotropy, fractional amplitude of low-frequency fluctuation, and functional connectivity (FC), were obtained for each participant and compared between the groups. RESULTS: Patients in both the groups exhibited widespread functional and diffusion abnormalities in the whole thalamus and several subregions, with more obvious changes observed in the effective group. All tinnitus patients had abnormal FC compared with the HCs; FC differences between the two patient groups were only observed in the striatal network, auditory-related cortex, and the core area of the limbic system. We combined the multimodal quantitative thalamic alterations and used it as an imaging indicator to evaluate prognosis before sound therapy and achieved a sensitivity of 71.9% and a specificity of 85.7%. CONCLUSION: Similar patterns of thalamic alterations were identified in tinnitus patients with different outcomes, with more obvious changes observed in the effective group. Our findings support the tinnitus generation hypothesis of frontostriatal gating system dysfunction. A combination of multimodal quantitative thalamic properties may be used as indicators to predict tinnitus prognosis before sound therapy.