Neuronal Functional Connectivity Research Articles

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

Distinct attentional profile and functional connectivity of neurons with visual feature coding in the primate brain.

Visual attention and object recognition are two critical cognitive functions that significantly influence our perception of the world. While these neural processes converge on the temporal cortex, the exact nature of their interactions remains largely unclear. Here, we systematically investigated the interplay between visual attention and object feature coding by training macaques to perform a free-gaze visual search task using natural face and object stimuli. With a large number of units recorded from multiple brain areas, we discovered that units exhibiting visual feature coding displayed a distinct attentional response profile and functional connectivity compared to units not exhibiting feature coding. Attention directed towards search targets enhanced the pattern separation of stimuli across brain areas, and this enhancement was more pronounced for units encoding visual features. Our findings suggest two stages of neural processing, with the early stage primarily focused on processing visual features and the late stage dedicated to processing attention. Importantly, feature coding in the early stage could predict the attentional effect in the late stage. Together, our results suggest an intricate interplay between visual feature and attention coding in the primate brain, which can be attributed to the differential functional connectivity and neural networks engaged in these processes.

Pain experience reduces social avoidance to others in pain: a c-Fos-based functional connectivity network study in mice.

Pain experience increases individuals' perception and contagion of others' pain, but whether pain experience affects individuals' affiliative or antagonistic responses to others' pain is largely unknown. Additionally, the neural mechanisms underlying how pain experience modulates individuals' responses to others' pain remain unclear. In this study, we explored the effects of pain experience on individuals' responses to others' pain and the underlying neural mechanisms. By comparing locomotion, social, exploration, stereotyped, and anxiety-like behaviors of mice without any pain experience (naïve observers) and mice with a similar pain experience (experienced observers) when they observed the pain-free demonstrator with intraperitoneal injection of normal saline and the painful demonstrator with intraperitoneal injection of acetic acid, we found that pain experience of the observers led to decreased social avoidance to the painful demonstrator. Through whole-brain c-Fos quantification, we discovered that pain experience altered neuronal activity and enhanced functional connectivity in the mouse brain. The analysis of complex network and graph theory exhibited that functional connectivity networks and activated hub regions were altered by pain experience. Together, these findings reveal that neuronal activity and functional connectivity networks are involved in the modulation of individuals' responses to others' pain by pain experience.

Effects of maternal supplementation with DHA and/or egg yolk powder on monoamine homeostasis in the perinatal piglet brain

ABSTRACT Objectives Reports indicate that children of mothers who received docosahexaenoic acid (DHA) or egg yolk supplements during pregnancy have improved performance on cognitive tasks and brain growth; their combination has recently been demonstrated to modulate functional neuronal network connectivity in the human-relevant piglet brain. To expand upon this functional connectivity analysis, neurochemical evaluation to determine how dietary supplementation with one or both of these nutrients during the last trimester of pregnancy alters monoamine homeostasis in selected brain regions of piglets was done. Methods Beginning gestation days 60–69 through weaning, pregnant sows were fed either control diet or diets supplemented with egg yolk powder, DHA, or both. Brains were then collected, and monoamine neurotransmitters and their metabolites were quantified from various brain regions with HPLC-ECD. Results Relative to controls, egg yolk supplementation increased serotonin metabolite (5-HIAA) levels in the cerebellum, while DHA supplementation decreased serotonin (5-HT) levels in the prefrontal cortex; combined supplementation increased norepinephrine metabolite (MHPG) levels in the prefrontal cortex and cerebellum, but decreased 5-HT levels in the posterior hippocampus. Notably, all diets increased serotonin, dopamine, and their respective metabolite levels in the substantia nigra. Disscussion This suggests both overlapping and specific effects of DHA and components of egg yolk in the context of maternal supplementation during pregnancy and lactation that might facilitate optimal neurodevelopment, with the nigrostriatal pathway being particularly sensitive. Such supplementations might impact brain function and facilitate development later in life through modulating monoamine homeostasis.

Effect of popular songs from the reminiscence bump as autobiographical memory cues in aging: a preliminary study using EEG.

Music has the capacity to evoke emotions and memories. This capacity is influenced by whether or not the music is from the reminiscence bump (RB) period. However, research on the neural correlates of the processes of evoking autobiographical memories through songs is scant. The aim of this study was to analyze the differences at the level of frequency band activation in two situations: (1) whether or not the song is able to generate a memory; and (2) whether or not the song is from the RB period. A total of 35 older adults (22 women, age range: 61-73 years) listened to 10 thirty-second musical clips that coincided with the period of their RB and 10 from the immediately subsequent 5 years (non-RB). To record the EEG signal, a brain-computer interface (BCI) with 14 channels was used. The signal was recorded during the 30-seconds of listening to each music clip. The results showed differences in the activation levels of the frequency bands in the frontal and temporal regions. It was also found that the non-retrieval of a memory in response to a song clip showed a greater activation of low frequency waves in the frontal region, compared to the trials that did generate a memory. These results suggest the importance of analyzing not only brain activation, but also neuronal functional connectivity at older ages, in order to better understand cognitive and emotional functions in aging.

Online Estimating Pairwise Neuronal Functional Connectivity in Brain-Machine Interface.

Neurons respond to external stimuli and form functional networks through pairwise interactions. A neural encoding model can describe a single neuron's behavior, and brain-machine interfaces (BMIs) provide a platform to investigate how neurons adapt, functionally connect, and encode movement. Movement modulation and pairwise functional connectivity are modeled as high-dimensional tuning states, estimated from neural spike train observations. However, accurate estimation of this neural state vector can be challenging as pairwise neural interactions are highly dimensional, change in different temporal scales from movement, and could be non-stationary. We propose an Adam-based gradient descent method to online estimate high-dimensional pairwise neuronal functional connectivity and single neuronal tuning adaptation simultaneously. By minimizing negative log-likelihood based on point process observation, the proposed method adaptively adjusts the learning rate for each dimension of the neural state vectors by employing momentum and regularizer. We test the method on real recordings of two rats performing the brain control mode of a two-lever discrimination task. Our results show that our method outperforms existing methods, especially when the state is sparse. Our method is more stable and faster for an online scenario regardless of the parameter initializations. Our method provides a promising tool to track and build the time-variant functional neural connectivity, which dynamically forms the functional network and results in better brain control.

Abnormal alterations of regional spontaneous neuronal activity and functional connectivity in insomnia patients with difficulty falling asleep: a resting-state fMRI study

BackgroundInsomnia disorder (ID) seriously affects people’s daily life. Difficulty falling asleep is the most commonly reported complaint in patients with ID. However, the mechanism of prolonged sleep latency (SL) is still obscure. The aim of our present study was to investigate the relationship between prolonged SL and alterations in spontaneous neural activity and brain functional connectivity (FC) in ID patients using functional magnetic resonance imaging (fMRI).MethodsA total of 52 insomniacs with difficulty falling asleep and 30 matched healthy controls (HCs) underwent resting-state fMRI. The amplitude of low-frequency fluctuation (ALFF) was measured and group differences were compared. The peak areas with significantly different ALFF values were identified as the seed regions to calculate FC to the whole brain. SL was assessed by a wrist actigraphy device in ID patients. The Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), and Hyperarousal Scale (HAS) were evaluated in both ID patients and HCs. Finally, correlation analyses were performed between the clinical features and FC/ALFF values.ResultsID patients showed higher PSQI, HAMA, HAS scores than HCs. The functional MRI results indicated increased ALFF value in the left insula and right amygdala and decreased ALFF value in the right superior parietal lobe (SPL) in ID patients. The seed-based FC analysis demonstrated increased FC between the left insula and the bilateral precentral gyrus and FC between the right amygdala and the left posterior cingulate cortex (PCC) in patients with ID. Correlation analysis indicated that the increased FC value of the right amygdala-left PCC was positively correlated with SL measured by actigraphy.ConclusionThis study revealed abnormal regional spontaneous fluctuations in the right amygdala, left insula, and right SPL, as well as increased FC in the left insula-precentral and right amygdala-left PCC. Moreover, the prolonged SL was positively correlated with the abnormal FC in the right amygdala-left PCC in ID patients. The current study showed the correlation between prolonged SL and the abnormal function of emotion-related brain regions in ID patients, which may contribute to a better understanding of the neural mechanisms underlying difficulty falling asleep in patients with ID.Clinical Trial Registrationhttp://www.chictr.org.cn., ChiCTR1800015282. Registered on 20th March 2018.

Subbotin graphical models for extreme value dependencies with applications to functional neuronal connectivity

Subbotin graphical models for extreme value dependencies with applications to functional neuronal connectivity

Electrical stimulation induced structural 3D human engineered neural tissue with well-developed neuronal network and functional connectivity

Objective. Three-dimensional (3D) neural tissue engineering is expected to provide new stride in developing neural disease models and functional substitutes to aid in the treatment of central nervous system injury. We have previously detailed an electrical stimulation (ES) system to generate 3D mouse engineered neural tissue (mENT) in vitro. However, ES-induced human ENT (hENT) has not previously been either investigated or identified in structural and functional manner. Here, we applied ES as a stimulator to regulate human neural stem cells in 3D Matrigel, explored the components and functional properties of hENTs. Approach. By immunofluorescence chemical staining and electron microscope imaging, we evaluated the effects of ES on (1) neuronal differentiation and maturation, (2) neurites outgrowth and alignment in hENT, (3) formation of synapses and myelin sheaths in hENT. We further investigated the formation of synaptic connections between ex-vivo-fused mouse and human tissue. We used calcium imaging to detect activities of neurons in hENT culture. Results. ES could induce neuronal differentiation, the orderly growth of neurites and the maturation of neuron subtypes to construct a well-developed neuronal network with synapses and myelin sheaths. Most importantly, we discovered that raising extracellular K+ concentration resulted the increasing neuronal excitability in the hENT, indicating electrical activities in neuronal cells. Significance. We applied ES to generate the organised 3D hENTs and identified them in both structural and functional manner.

Abnormal regional spontaneous neural activity and functional connectivity in thyroid-associated ophthalmopathy patients with different activity: a resting-state fMRI study.

We aimed to evaluate the spontaneous neuronal activity and functional connectivity pattern variations using resting-state functional magnetic resonance imaging (rs-fMRI) measures, such as amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF), and functional connectivity (FC), in patients with thyroid-associated ophthalmopathy (TAO). A total of 24 active TAO patients, 26 inactive TAO patients, and 27 matched healthy controls (HCs) were included. First, ALFF and fALFF were used to detect local neural activity changes, the MRI data were analyzed, and regions with group differences were taken as seeds. Second, FC analysis was performed to explore the altered connection between seeds and other brain regions. A correlation analysis was performed to assess the relationship between functional brain activity and clinical indices and neuropsychiatric behaviors. Compared to HCs, both active and inactive TAO patients exhibited significantly lower ALFF values in the right calcarine (Calcarine_R) and left postcentral gyrus (Postcentral_L). Active TAO patients also showed significantly higher ALFF values in the left caudate nucleus (Caudate_L) and increased fALFF values in the superior lobe of the right cerebellum (Cerebelum_Crus1_R). Moreover, both active and inactive TAO patients demonstrated decreased FC within the left postcentral gyrus (Postcentral_L) compared to HCs. Additionally, active TAO patients exhibited lower FC compared to inactive TAO patients. The ALFF values in the Calcarine_R of active TAO patients positively correlated with disease duration (r = 0.5892, p = 0.0049) and the Hamilton Anxiety Rating Scale (HARS; r = 0.5377, p = 0.0119). Furthermore, the ALFF value in the Calcarine_R of inactive TAO patients negatively correlated with visual functioning (r = -0.5449, p = 0.0072), while the ALFF values in the Caudate_L of active TAO patients positively correlated with visual functioning (r = 0.6496, p = 0.0014). We found that the Caudate_L and Cerebelum_Crus1_R related to motor control and coordination in active TAO patients exhibit significant compensatory mechanisms; whereas, the Calcarine_R and Postcentral_L related to visual and somatosensory cortices show varying degrees of impairment. Our findings complement the functional neural mechanism of TAO.

Early retinal deprivation crossmodally alters nascent subplate circuits and activity in the auditory cortex during the precritical period.

Sensory perturbation in one modality results in the adaptive reorganization of neural pathways within the spared modalities, a phenomenon known as "crossmodal plasticity," which has been examined during or after the classic "critical period." Because peripheral perturbations can alter the auditory cortex (ACX) activity and functional connectivity of the ACX subplate neurons (SPNs) even before the critical period, called the precritical period, we investigated if retinal deprivation at birth crossmodally alters the ACX activity and SPN circuits during the precritical period. We deprived newborn mice of visual inputs after birth by performing bilateral enucleation. We performed in vivo widefield imaging in the ACX of awake pups during the first two postnatal weeks to investigate cortical activity. We found that enucleation alters spontaneous and sound-evoked activities in the ACX in an age-dependent manner. Next, we performed whole-cell patch clamp recording combined with laser scanning photostimulation in ACX slices to investigate circuit changes in SPNs. We found that enucleation alters the intracortical inhibitory circuits impinging on SPNs, shifting the excitation-inhibition balance toward excitation and this shift persists after ear opening. Together, our results indicate that crossmodal functional changes exist in the developing sensory cortices at early ages before the onset of the classic critical period.

Systems-level analysis of local field potentials reveals differential effects of lysergic acid diethylamide and ketamine on neuronal activity and functional connectivity.

Psychedelic substances have in recent years attracted considerable interest as potential treatments for several psychiatric conditions, including depression, anxiety, and addiction. Imaging studies in humans point to a number of possible mechanisms underlying the acute effects of psychedelics, including changes in neuronal firing rates and excitability as well as alterations in functional connectivity between various brain nodes. In addition, animal studies using invasive recordings, have suggested synchronous high-frequency oscillations involving several brain regions as another key feature of the psychedelic brain state. To better understand how the imaging data might be related to high-resolution electrophysiological measurements, we have here analyzed the aperiodic part of the local field potential (LFP) in rodents treated with a classic psychedelic (LSD) or a dissociative anesthetic (ketamine). In addition, functional connectivity, as quantified by mutual information measures in the LFP time series, has been assessed with in and between different structures. Our data suggest that the altered brain states of LSD and ketamine are caused by different underlying mechanisms, where LFP power shifts indicate increased neuronal activity but reduced connectivity following ketamine, while LSD also leads to reduced connectivity but without an accompanying change in LFP broadband power.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

Basal forebrain cholinergic signalling: development, connectivity and roles in cognition.

Acetylcholine plays an essential role in fundamental aspects of cognition. Studies that have mapped the activity and functional connectivity of cholinergic neurons have shown that the axons of basal forebrain cholinergic neurons innervate the pallium with far more topographical and functional organization than was historically appreciated. Together with the results of studies using new probes that allow release of acetylcholine to be detected with high spatial and temporal resolution, these findings have implicated cholinergic networks in 'binding' diverse behaviours that contribute to cognition. Here, we review recent findings on the developmental origins, connectivity and function of cholinergic neurons, and explore the participation of cholinergic signalling in the encoding of cognition-related behaviours.

Hippocampal Neuronal Integrity and Functional Connectivity Within the Default Mode Network in Mild Cognitive Impairment: A Multimodal Investigation.

Background: In older people with mild cognitive impairment (MCI), the relationship between early changes in functional connectivity and in vivo changes in key neurometabolites is not known. Two established correlates of MCI diagnosis are decreased N-acetylaspartate (NAA) in the hippocampus, indicative of decreased neuronal integrity, and changes in the default mode network (DMN) functional network. If and how these measures interrelate is yet to be established, and such understanding may provide insight into the processes underpinning observed cognitive decline. Objectives: To determine the relationship between NAA levels in the left hippocampus and functional connectivity within the DMN in an aging cohort. Methods: In a sample of 51 participants with MCI and 30 controls, hippocampal NAA was determined using magnetic resonance spectroscopy, and DMN connectivity was quantified using resting-state functional MRI. The association between hippocampal NAA and the DMN functional connectivity was tested within the MCI group and separately within the control group. Results: In the DMN, we showed a significant inverse association between functional connectivity and hippocampal NAA in 20 specific brain connections for patients with MCI. This was despite no evidence of any associations in the healthy control group or group differences in either of these measures alone. Conclusions: This study suggests that decreased neuronal integrity in the hippocampus is associated with functional change within the DMN for those with MCI, in contrast to healthy older adults. These results highlight the potential of multimodal investigations to better understand the processes associated with cognitive decline. Impact statement This study measured activity within the default mode network (DMN) and quantified N-acetylaspartate (NAA), a measure of neuronal integrity, within the hippocampus in participants with mild cognitive impairment (MCI) and healthy controls. In participants with MCI, NAA levels were inversely associated with connectivity between specific regions of the DMN, a relationship not evident in healthy controls. This association was present even in the absence of group differences in DMN connectivity or NAA levels. This research illustrates the possibility of using multiple magnetic resonance modalities for more sensitive measures of early cognitive decline to identify and intervene earlier.

Low intensity repetitive transcranial magnetic stimulation modulates brain-wide functional connectivity to promote anti-correlated c-Fos expression

Repetitive transcranial magnetic stimulation (rTMS) induces action potentials to induce plastic changes in the brain with increasing evidence for the therapeutic importance of brain-wide functional network effects of rTMS; however, the influence of sub-action potential threshold (low-intensity; LI-) rTMS on neuronal activity is largely unknown. We investigated whether LI-rTMS modulates neuronal activity and functional connectivity and also specifically assessed modulation of parvalbumin interneuron activity. We conducted a brain-wide analysis of c-Fos, a marker for neuronal activity, in mice that received LI-rTMS to visual cortex. Mice received single or multiple sessions of excitatory 10 Hz LI-rTMS with custom rodent coils or were sham controls. We assessed changes to c-Fos positive cell densities and c-Fos/parvalbumin co-expression. Peak c-Fos expression corresponded with activity during rTMS. We also assessed functional connectivity changes using brain-wide c-Fos-based network analysis. LI-rTMS modulated c-Fos expression in cortical and subcortical regions. c-Fos density changes were most prevalent with acute stimulation, however chronic stimulation decreased parvalbumin interneuron activity, most prominently in the amygdala and striatum. LI-rTMS also increased anti-correlated functional connectivity, with the most prominent effects also in the amygdala and striatum following chronic stimulation. LI-rTMS induces changes in c-Fos expression that suggest modulation of neuronal activity and functional connectivity throughout the brain. Our results suggest that LI-rTMS promotes anticorrelated functional connectivity, possibly due to decreased parvalbumin interneuron activation induced by chronic stimulation. These changes may underpin therapeutic rTMS effects, therefore modulation of subcortical activity supports rTMS for treatment of disorders involving subcortical dysregulation.

Normalized compression distance to measure cortico-muscular synchronization.

The neuronal functional connectivity is a complex and non-stationary phenomenon creating dynamic networks synchronization determining the brain states and needed to produce tasks. Here, as a measure that quantifies the synchronization between the neuronal electrical activity of two brain regions, we used the normalized compression distance (NCD), which is the length of the compressed file constituted by the concatenated two signals, normalized by the length of the two compressed files including each single signal. To test the NCD sensitivity to physiological properties, we used NCD to measure the cortico-muscular synchronization, a well-known mechanism to control movements, in 15 healthy volunteers during a weak handgrip. Independently of NCD compressor (Huffman or Lempel Ziv), we found out that the resulting measure is sensitive to the dominant-non dominant asymmetry when novelty management is required (p = 0.011; p = 0.007, respectively) and depends on the level of novelty when moving the non-dominant hand (p = 0.012; p = 0.024). Showing lower synchronization levels for less dexterous networks, NCD seems to be a measure able to enrich the estimate of functional two-node connectivity within the neuronal networks that control the body.

PDE2A Inhibition Enhances Axonal Sprouting, Functional Connectivity, and Recovery after Stroke.

Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP response element-binding protein (CREB), which controls neuronal excitability and growth responses. CREB gain of function enhances learning and allocates neurons into memory engrams. CREB also controls recovery after stroke. PDE inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair, and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct, and functional disconnection of neuronal networks. PDE2A inhibition enhances functional recovery, increases axonal projections in peri-infarct cortex, and, through two-photon in vivo imaging, enhances the functional connectivity of motor system excitatory neurons. PDE2A inhibition after stroke does not have an effect on other aspects of tissue repair, such as angiogenesis, gliogenesis, neurogenesis, and inflammatory responses. These data suggest that PDE2A inhibition is an effective therapeutic approach for stroke recovery in the rodent and that it simultaneously enhances connectivity in peri-infarct neuronal populations.SIGNIFICANCE STATEMENT Inhibition of PDE2A enhances motor recovery, axonal projections, and functional connectivity of neurons in peri-infarct tissue. This represents an avenue for a pharmacological therapy for stroke recovery.

Brain-wide neuronal activation and functional connectivity are modulated by prior exposure to repetitive learning episodes.

Memory storage and retrieval are shaped by past experiences. Prior learning and memory episodes have numerous impacts on brain structure from micro to macroscale. Previous experience with specific forms of learning increases the efficiency of future learning. It is less clear whether such practice effects on one type of memory might also have transferable effects to other forms of memory. Different forms of learning and memory rely on different brain-wide networks but there are many points of overlap in these networks. Enhanced structural or functional connectivity caused by one type of learning may be transferable to another type of learning due to overlap in underlying memory networks. Here, we investigated the impact of prior chronic spatial training on the task-specific functional connectivity related to subsequent contextual fear memory recall in mice. Our results show that mice exposed to prior spatial training exhibited decreased brain-wide activation compared to control mice during the retrieval of a context fear memory. With respect to functional connectivity, we observed changes in several network measures, notably an increase in global efficiency. Interestingly, we also observed an increase in network resilience based on simulated targeted node deletion. Overall, this study suggests that chronic learning has transferable effects on the functional connectivity networks of other types of learning and memory. The generalized enhancements in network efficiency and resilience suggest that learning itself may protect brain networks against deterioration.