Multiscale neural signatures of major depressive, anxiety, and stress-related disorders.

The extent of shared and distinct neural mechanisms underlying major depressive disorder (MDD), anxiety, and stress-related disorders is still unclear. We compared the neural signatures of these disorders in 5,405 UK Biobank patients and 21,727 healthy controls. We found the greatest case­control differences in resting-state functional connectivity and cortical thickness in MDD, followed by anxiety and stress-related disorders. Neural signatures for MDD and anxiety disorders were highly concordant, whereas stress-related disorders showed a distinct pattern. Controlling for cross-disorder genetic risk somewhat decreased the similarity between functional neural signatures of stress-related disorders and both MDD and anxiety disorders. Among cases and healthy controls, reduced within-network and increased between-network frontoparietal and default mode connectivity were associated with poorer cognitive performance (processing speed, attention, associative learning, and fluid intelligence). These results provide evidence for distinct neural circuit function impairments in MDD and anxiety disorders compared to stress disorders, yet cognitive impairment appears unrelated to diagnosis and varies with circuit function.

Can internet use become addictive?

Problematic internet use parallels drug addiction, but the mechanisms are not yet clear.

Mapping dopaminergic projections in the human brain with resting-state fMRI.

The striatum receives dense dopaminergic projections, making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson's disease (PD) and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that 'connectopic mapping' - a novel approach for characterizing fine-grained, overlapping modes of functional connectivity - can be used to map dopaminergic projections in striatum. We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N = 839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a high spatial correlation (r = 0.884) with dopamine transporter availability - a marker of dopaminergic projections - derived from DaT SPECT scans of 209 healthy controls. Next, we obtained the subject-specific second-order modes from 20 controls and 39 PD patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed dopaminergic marker tracks PD diagnosis, symptom severity, and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers, we establish strong associations with self-reported alcohol and nicotine use. Our findings provide evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in PD symptom severity and L-DOPA sensitivity, and exhibits strong associations with levels of nicotine and alcohol use, thereby offering a new biomarker for dopamine-related (dys)function in the human brain.

Magnetoencephalography detects phase-amplitude coupling in Parkinson's disease.

To characterize Parkinson's disease, abnormal phase-amplitude coupling is assessed in the cortico-basal circuit using invasive recordings. It is unknown whether the same phenomenon might be found in regions other than the cortico-basal ganglia circuit. We hypothesized that using magnetoencephalography to assess phase-amplitude coupling in the whole brain can characterize Parkinson's disease. We recorded resting-state magnetoencephalographic signals in patients with Parkinson's disease and in healthy age- and sex-matched participants. We compared whole-brain signals from the two groups, evaluating the power spectra of 3 frequency bands (alpha, 8-12 Hz; beta, 13-25 Hz; gamma, 50-100 Hz) and the coupling between gamma amplitude and alpha or beta phases. Patients with Parkinson's disease showed significant beta-gamma phase-amplitude coupling that was widely distributed in the sensorimotor, occipital, and temporal cortices; healthy participants showed such coupling only in parts of the somatosensory and temporal cortices. Moreover, beta- and gamma-band power differed significantly between participants in the two groups (P < 0.05). Finally, beta-gamma phase-amplitude coupling in the sensorimotor cortices correlated significantly with motor symptoms of Parkinson's disease (P < 0.05); beta- and gamma-band power did not. We thus demonstrated that beta-gamma phase-amplitude coupling in the resting state characterizes Parkinson's disease.

NAc-VTA circuit underlies emotional stress-induced anxiety-like behavior in the three-chamber vicarious social defeat stress mouse model.

Emotional stress is considered a severe pathogenetic factor of psychiatric disorders. However, the circuit mechanisms remain largely unclear. Using a three-chamber vicarious social defeat stress (3C-VSDS) model in mice, we here show that chronic emotional stress (CES) induces anxiety-like behavior and transient social interaction changes. Dopaminergic neurons of ventral tegmental area (VTA) are required to control this behavioral deficit. VTA dopaminergic neuron hyperactivity induced by CES is involved in the anxiety-like behavior in the innate anxiogenic environment. Chemogenetic activation of VTA dopaminergic neurons directly triggers anxiety-like behavior, while chemogenetic inhibition of these neurons promotes resilience to the CES-induced anxiety-like behavior. Moreover, VTA dopaminergic neurons receiving nucleus accumbens (NAc) projections are activated in CES mice. Bidirectional modulation of the NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior. In conclusion, we propose that a NAc-VTA circuit critically establishes and regulates the CES-induced anxiety-like behavior. This study not only characterizes a preclinical model that is representative of the nuanced aspect of CES, but also provides insight to the circuit-level neuronal processes that underlie empathy-like behavior.

Neural coupling between upper and lower limb muscles in Parkinsonian gait.

OBJECTIVE: To explore to what extent neuronal coupling between upper and lower limb muscles during gait is preserved or affected in patients with Parkinson's Disease (PD). METHODS: Electromyography recordings were obtained from the bilateral deltoideus anterior and bilateral rectus femoris and biceps femoris muscles during overground gait in 20 healthy participants (median age 69 years) and 20 PD patients (median age 68.5 years). PD patients were able to walk independently (Hoehn and Yahr scale: Stage 2-3), had an equally distributed symptom laterality (6 left side, 7 both sides and 7 right side) and no cognitive problems or tremor dominant PD. Time-dependent directional intermuscular coherence analysis was employed to compare the neural coupling between upper and lower limb muscles between healthy participants and PD patients in three different directions: zero-lag (i.e. common driver), forward (i.e. shoulders driving the legs) and reverse component (i.e. legs driving the shoulders). RESULTS: Compared to healthy participants, PD patients exhibited (i) reduced intermuscular zero-lag coherence in the beta/gamma frequency band during end-of-stance and (ii) enhanced forward as well as reverse directed coherence in the alpha and beta/gamma frequency bands around toe-off. CONCLUSIONS: PD patients had a reduced common cortical drive to upper and lower limb muscles during gait, possibly contributing to disturbed interlimb coordination. Enhanced bidirectional coupling between upper and lower limb muscles on subcortical and transcortical levels in PD patients suggests a mechanism of compensation. SIGNIFICANCE: These findings provide support for the facilitating effect of arm swing instructions in PD gait.

Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models.

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

Neonatal brain injury influences structural connectivity and childhood functional outcomes.

Neonatal brain injury may impact brain development and lead to lifelong functional impairments. Hypoxic-ischemic encephalopathy (HIE) and congenital heart disease (CHD) are two common causes of neonatal brain injury differing in timing and mechanism. Maturation of whole-brain neural networks can be quantified during development using diffusion magnetic resonance imaging (dMRI) in combination with graph theory metrics. DMRI of 35 subjects with CHD and 62 subjects with HIE were compared to understand differences in the effects of HIE and CHD on the development of network topological parameters and functional outcomes. CHD newborns had worse 12-18 month language (P<0.01) and 30 month cognitive (P<0.01), language (P = 0.05), motor outcomes (P = 0.01). Global efficiency, a metric of brain integration, was lower in CHD (P = 0.03) than in HIE, but transitivity, modularity and small-worldness were similar. After controlling for clinical factors known to affect neurodevelopmental outcomes, we observed that global efficiency was highly associated with 30 month motor outcomes (P = 0.02) in both groups. To explore neural correlates of adverse language outcomes in CHD, we used hypothesis-based and data-driven approaches to identify pathways with altered structural connectivity. We found that connectivity strength in the superior longitudinal fasciculus (SLF) tract 2 was inversely associated with expressive language. After false discovery rate correction, a whole connectome edge analysis identified 18 pathways that were hypoconnected in the CHD cohort as compared to HIE. In sum, our study shows that neonatal structural connectivity predicts early motor development after HIE or in subjects with CHD, and regional SLF connectivity is associated with language outcomes. Further research is needed to determine if and how brain networks change over time and whether those changes represent recovery or ongoing dysfunction. This knowledge will directly inform strategies to optimize neurologic functional outcomes after neonatal brain injury.

Changes in ventromedial prefrontal cortex functional connectivity are correlated with increased risk-taking after total sleep deprivation.

There is evidence indicating that people are more likely to take risks when they are sleep-deprived than during resting wakefulness (RW). The ventromedial prefrontal cortex (vmPFC) could have a crucial psychophysiological role in this phenomenon. However, the intrinsic patterns of functional organization of the human vmPFC and their relationship with risk-taking during sleep deprivation (SD) are unclear. This study investigated the relationship between functional connectivity in the vmPFC and cerebral cortex and the risk-taking tendency after SD. The study participants were 21 healthy college students who underwent functional magnetic resonance imaging twice in the resting state, once during RW and once after 36 h of SD. The vmPFC was analyzed bilaterally for functional connectivity between the regions of interest. Correlation analysis was performed to evaluate changes in functional connectivity between the vmPFC and the cerebral cortex and risk-taking before and after SD. A single night of SD produced a definite deficit in functional connectivity between the vmPFC and thalamus bilaterally and an increase in functional connectivity between the vmPFC and dorsolateral prefrontal cortex (dlPFC) and the parietal lobe. We also found that the likelihood of risk-taking was positively correlated with increased functional connectivity between the vmPFC and dlPFC and negatively correlated with decreased functional connectivity between the vmPFC and thalamus bilaterally. These results demonstrate that lack of sleep substantially impairs functional connectivity between the vmPFC and the cerebral cortex, which in turn predicts the risk-taking behavior found after SD.

Brain Mechanisms of Pain and Dysautonomia in Diabetic Neuropathy: Connectivity Changes in Thalamus and Hypothalamus.

CONTEXT: About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. OBJECTIVE: This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. METHODS: We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. RESULTS: The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. CONCLUSION: Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

Nicotine modulation of the lateral habenula/ventral tegmental area circuit dynamics: An electrophysiological study in rats.

Nicotine, the addictive component of tobacco, has bivalent rewarding and aversive properties. Recently, the lateral habenula (LHb), a structure that controls ventral tegmental area (VTA) dopamine (DA) function, has attracted attention as it is potentially involved in the aversive properties of drugs of abuse. Hitherto, the LHb-modulation of nicotine-induced VTA neuronal activity in vivo is unknown. Using standard single-extracellular recording in anesthetized rats, we observed that intravenous administration of nicotine hydrogen tartrate (25-800 µg/kg i.v.) caused a dose-dependent increase in the basal firing rate of the LHb neurons of nicotine-naïve rats. This effect underwent complete desensitization in chronic nicotine (6 mg/kg/day for 14 days)-treated animals. As previously reported, acute nicotine induced an increase in the VTA DA neuronal firing rate. Interestingly, only neurons located medially (mVTA) but not laterally (latVTA) within the VTA were responsive to acute nicotine. This pattern of activation was reversed by chronic nicotine exposure which produced the selective increase of latVTA neuronal activity. Acute lesion of the LHb, similarly to chronic nicotine treatment, reversed the pattern of DA cell activation induced by acute nicotine increasing latVTA but not mVTA neuronal activity. Our evidence indicates that LHb plays an important role in mediating the effects of acute and chronic nicotine within the VTA by activating distinct subregional responses of DA neurons. The LHb/VTA modulation might be part of the neural substrate of nicotine aversive properties. By silencing the LHb chronic nicotine could shift the balance of motivational states toward the reward.

Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?

For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.

Cross-modal connectivity effects in age-related hearing loss.

Age-related sensorineural hearing loss (HL) leads to localized brain changes in the primary auditory cortex, long-range functional alterations, and is considered a risk factor for dementia. Nonhuman studies have repeatedly highlighted cross-modal brain plasticity in sensorial brain networks other than those primarily involved in the peripheral damage, thus in this study, the possible cortical alterations associated with HL have been analyzed using a whole-brain multimodal connectomic approach. Fifty-two HL and 30 normal hearing participants were examined in a 3T MRI study along with audiological and neurological assessments. Between-regions functional connectivity and whole-brain probabilistic tractography were calculated in a connectome-based manner and graph theory was used to obtain low-dimensional features for the analysis of brain connectivity at global and local levels. The HL condition was associated with a different functional organization of the visual subnetwork as revealed by a significant increase in global efficiency, density, and clustering coefficient. These functional effects were mirrored by similar (but more subtle) structural effects suggesting that a functional repurposing of visual cortical centers occurs to compensate for age-related loss of hearing abilities.

Exploring propriospinal neuron-mediated neural circuit plasticity using recombinant viruses after spinal cord injury.

Propriospinal neurons (PSNs) play a crucial role in motor control and sensory processing and contribute to plastic reorganization of spinal circuits responsible for recovery from spinal cord injury (SCI). Due to their scattered distribution and various intersegmental projection patterns, it is challenging to dissect the function of PSNs within the neuronal network. New genetically encoded tools, particularly cell-type-specific transgene expression methods using recombinant viral vectors combined with other genetic, pharmacologic, and optogenetic approaches, have enormous potential for visualizing PSNs in the neuronal circuits and monitoring and manipulating their activity. Furthermore, recombinant viral tools have been utilized to promote the intrinsic regenerative capacities of PSNs, towards manipulating the 'hostile' microenvironment for improving functional regeneration of PSNs. Here we summarize the latest development in this fast-moving field and provide a perspective for using this technology to dissect PSN physiological role in contributing to recovery of function after SCI.

Descending pain modulatory efficiency in healthy subjects is related to structure and resting connectivity of brain regions.

The descending pain modulatory system in humans is commonly investigated using conditioned pain modulation (CPM). Whilst variability in CPM efficiency, i.e., inhibition and facilitation, is normal in healthy subjects, exploring the inter-relationship between brain structure, resting-state functional connectivity (rsFC) and CPM readouts will provide greater insight into the underlying CPM efficiency seen in healthy individuals. Thus, this study combined CPM testing, voxel-based morphometry (VBM) and rsFC to identify the neural correlates of CPM in a cohort of healthy subjects (n =40), displaying pain inhibition (n = 29), facilitation (n = 10) and no CPM effect (n = 1). Clusters identified in the VBM analysis were implemented in the rsFC analysis alongside key constituents of the endogenous pain modulatory system. Greater pain inhibition was related to higher volume of left frontal cortices and stronger rsFC between the motor cortex and periaqueductal grey. Conversely, weaker pain inhibition was related to higher volume of the right frontal cortex - coupled with stronger rsFC to the primary somatosensory cortex, and rsFC between the amygdala and posterior insula. Overall, healthy subjects showed higher volume and stronger rsFC of brain regions involved with descending modulation, while the lateral and medial pain systems were related to greater pain inhibition and facilitation during CPM, respectively. These findings reveal structural alignments and functional interactions between supraspinal areas involved in CPM efficiency. Ultimately understanding these underlying variations and how they may become affected in chronic pain conditions, will advance a more targeted subgrouping in pain patients for future cross-sectional studies investigating endogenous pain modulation.

Altered resting-state functional connectivity of the frontal-striatal circuit in elderly with apathy.

Apathy is defined as reduction of goal-directed behaviors and a common nuisance syndrome of neurodegenerative and psychiatric disease. The underlying mechanism of apathy implicates changes of the front-striatal circuit, but its precise alteration is unclear for apathy in healthy aged people. The aim of our study is to investigate how the frontal-striatal circuit is changed in elderly with apathy using resting-state functional MRI. Eighteen subjects with apathy (7 female, 63.7 ± 3.0 years) and eighteen subjects without apathy (10 female, 64.8 ± 3.0 years) who underwent neuropsychological assessment and MRI measurement were recruited. We compared functional connectivity with/within the striatum between the apathy and non-apathy groups. The seed-to-voxel group analysis for functional connectivity between the striatum and other brain regions showed that the connectivity was decreased between the ventral rostral putamen and the right dorsal anterior cingulate cortex/supplementary motor area in the apathy group compared to the non-apathy group while the connectivity was increased between the dorsal caudate and the left sensorimotor area. Moreover, the ROI-to-ROI analysis within the striatum indicated reduction of functional connectivity between the ventral regions and dorsal regions of the striatum in the apathy group. Our findings suggest that the changes in functional connectivity balance among different frontal-striatum circuits contribute to apathy in elderly.

Enhancing neural markers of attention in children with ADHD using a digital therapeutic.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition characterized by diminished attentional control. Critically, these difficulties are related to negative consequences in real-life functioning both during development and into adulthood. There is now growing evidence that modulating the underlying neural circuits related to attention can improve behavior and brain function in children with ADHD. We have previously shown that game-based digital therapeutics targeting a key neural marker of attention-midline frontal theta (MFT)-yield positive effects on attentional control in several populations. However, the effects of such digital therapeutics in children with ADHD and no other comorbidities has not been yet examined. To address this gap, we assessed a sample of 25 children with ADHD (8-12 years old) on neural, behavioral, and clinical metrics of attention before and after a 4-week at-home intervention on an iPad targeting MFT circuitry. We found that children showed enhancements on a neural measure of attention (MFT power), as well as on objective behavioral measures of attention and parent reports of clinical ADHD symptoms. Importantly, we observed relationships between the neural and behavioral cognitive improvements, demonstrating that those children who showed the largest intervention-related neural gains were also those that improved the most on the behavioral tasks indexing attention. These findings provide support for using targeted, digital therapeutics to enhance multiple features of attentional control in children with ADHD. Study registration: ClinicalTrials.gov registry (NCT03844269) https://clinicaltrials.gov/ct2/show/NCT03844269.

Neural correlates of product attachment to cosmetics.

The neurobiological basis of brand and product attachment has received much attention in consumer neuroscience research, although it remains unclear. In this study, we conducted functional MRI experiments involving female users of famous luxury brand cosmetics as participants, based on the regions of interest involved in human attachment and object attachment. The results showed that the left ventral pallidum (VP), which is involved in positive reward, and the right posterior cingulate cortex (PCC), which is involved in self-concept, a key concept in object attachment, are the core regions in cosmetic attachment. Moreover, the performed psychophysiological interaction analyses showed that VP-temporoparietal junction connectivity positively correlated with activity in the dorsal raphe nucleus, and PCC-anterior hippocampus (aHC) connectivity positively correlated with subjective evaluation of attachment. The former suggests that object attachment is a human-like attachment and a stronger tendency of anthropomorphism is associated with stronger feelings of security. The latter suggests that the individual's concept of attachment as well as the relationships with the attached cosmetics are represented in the aHC, and the PCC-aHC associations produce subjective awareness of the attachment relationships. These associations between memory and reward systems have been shown to play critical roles in cosmetic attachment.

Structural and functional connectivity of the ascending arousal network for prediction of outcome in patients with acute disorders of consciousness.

To determine the role of early acquisition of blood oxygen level-dependent (BOLD) signals and diffusion tensor imaging (DTI) for analysis of the connectivity of the ascending arousal network (AAN) in predicting neurological outcomes after acute traumatic brain injury (TBI), cardiopulmonary arrest (CPA), or stroke. A prospective analysis of 50 comatose patients was performed during their ICU stay. Image processing was conducted to assess structural and functional connectivity of the AAN. Outcomes were evaluated after 3 and 6 months. Nineteen patients (38%) had stroke, 18 (36%) CPA, and 13 (26%) TBI. Twenty-three patients were comatose (44%), 11 were in a minimally conscious state (20%), and 16 had unresponsive wakefulness syndrome (32%). Univariate analysis demonstrated that measurements of diffusivity, functional connectivity, and numbers of fibers in the gray matter, white matter, whole brain, midbrain reticular formation, and pontis oralis nucleus may serve as predictive biomarkers of outcome depending on the diagnosis. Multivariate analysis demonstrated a correlation of the predicted value and the real outcome for each separate diagnosis and for all the etiologies together. Findings suggest that the above imaging biomarkers may have a predictive role for the outcome of comatose patients after acute TBI, CPA, or stroke.