Conor Liston

Imaging the developing brain: what have we learned about cognitive development?

The human brain undergoes significant changes in both its structural architecture and functional organization across the life span. Advances in neuroimaging techniques over the past decade have allowed us to track these changes safely in the human in vivo. We review the imaging literature on the neurobiology of cognitive development, focusing specifically on cognitive task-dependent changes observed in brain physiology and anatomy across childhood and adolescence. The findings suggest that cortical function becomes fine-tuned with development. Brain regions associated with more basic functions such as sensory and motor processes mature first, followed by association areas involved in top-down control of behavior.

Stress-Induced Alterations in Prefrontal Cortical Dendritic Morphology Predict Selective Impairments in Perceptual Attentional Set-Shifting

Stressful life events have been implicated clinically in the pathogenesis of mental illness, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of these psychiatric conditions are associated with structural and functional abnormalities in a network of prefrontal cortical structures. Here, we examine whether chronic stress-induced dendritic alterations in the medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) underlie impairments in the behaviors that they subserve. After 21 d of repeated restraint stress, rats were tested on a perceptual attentional set-shifting task, which yields dissociable measures of reversal learning and attentional set-shifting, functions that are mediated by the OFC and mPFC, respectively. Intracellular iontophoretic injections of Lucifer yellow were performed in a subset of these rats to examine dendritic morphology in layer II/III pyramidal cells of the mPFC and lateral OFC. Chronic stress induced a selective impairment in attentional set-shifting and a corresponding retraction (20%) of apical dendritic arbors in the mPFC. In stressed rats, but not in controls, decreased dendritic arborization in the mPFC predicted impaired attentional set-shifting performance. In contrast, stress was not found to adversely affect reversal learning or dendritic morphology in the lateral OFC. Instead, apical dendritic arborization in the OFC was increased by 43%. This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.

A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human

Of Mice and Men Just how closely must mouse models replicate the known features of human disorders to be accepted as useful for mechanistic and therapeutic studies? Soliman et al. (p. 863, published online 14 January) compared mice that vary only in their allelic composition at one position within the gene encoding brain-derived neurotrophic factor (BDNF) with humans exhibiting the same range of allelic variation. Individuals (mice and humans) carrying the allele that codes for a methionine-containing variant of BDNF retained a fearful response to a threatening stimulus even after its removal in comparison to those with the valine variant. Furthermore, in both cases, this linkage was mediated by diminished activity in the ventral-medial region of the prefrontal cortex. This deficit in extinction learning may contribute to differential responses to extinction-based therapies for anxiety disorders. A common genetic variation affecting fear learning and extinction operates through the same pathways in mice and men. Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

Psychosocial stress reversibly disrupts prefrontal processing and attentional control

Relatively little is known about the long-term neurobiological sequelae of chronic stress, which predisposes susceptible patients to neuropsychiatric conditions affecting the prefrontal cortex (PFC). Animal models and human neuroimaging experiments provide complementary insights, yet efforts to integrate the two are often complicated by limitations inherent in drawing comparisons between unrelated studies with disparate designs. Translating from a rodent model of chronic stress where we have shown reversible disruption of PFC function, we show that psychosocial stress induces long-lasting but reversible impairments in behavioral and functional magnetic resonance imaging (fMRI) measures of PFC function in humans. Twenty healthy adults, exposed to 1 month of psychosocial stress, confirmed by a validated rating scale, were scanned while performing a PFC-dependent attention-shifting task. One month later, they returned for a second scanning session after a period of reduced stress, and their performance was compared with a twice-scanned, matched group of low-stress controls. Psychosocial stress selectively impaired attentional control and disrupted functional connectivity within a frontoparietal network that mediates attention shifts. These effects were reversible: after one month of reduced stress, the same subjects showed no significant differences from controls. These results highlight the plasticity of PFC networks in healthy human subjects and suggest one mechanism by which disrupted plasticity may contribute to cognitive impairments characteristic of stress-related neuropsychiatric conditions in susceptible individuals.

Anterior Cingulate and Posterior Parietal Cortices Are Sensitive to Dissociable Forms of Conflict in a Task-Switching Paradigm

The conflict-monitoring hypothesis posits that anterior cingulate cortex (ACC) monitors conflict in information processing and recruits dorsolateral prefrontal cortex (DLPFC) to resolve competition as needed. We used fMRI to test this prediction directly in the context of a task-switching paradigm, in which subjects responded to the color or the motion of a visual stimulus. Conflict was indexed in terms of the product of activities in areas specialized for color or motion processing on a trial-by-trial basis. Here, we report that ACC and posterior parietal cortex (PPC) were sensitive to distinct forms of conflict, at the level of the response and the stimulus representation, respectively. Activity in PPC preceded increased activity in DLPFC and predicted enhanced behavioral performance on subsequent trials. These findings suggest that ACC and PPC may act in concert to detect dissociable forms of conflict and signal to DLPFC the need for increased control.

Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo

Glucocorticoids are a family of hormones that coordinate diverse physiological processes in responding to stress. Prolonged glucocorticoid exposure over weeks has been linked to dendritic atrophy and spine loss in fixed tissue studies of adult brains, but it is unclear how glucocorticoids may affect the dynamic processes of dendritic spine formation and elimination in vivo. Furthermore, relatively few studies have examined the effects of stress and glucocorticoids on spines during the postnatal and adolescent period, which is characterized by rapid synaptogenesis followed by protracted synaptic pruning. To determine whether and to what extent glucocorticoids regulate dendritic spine development and plasticity, we used transcranial two-photon microscopy to track the formation and elimination of dendritic spines in vivo after treatment with glucocorticoids in developing and adult mice. Corticosterone, the principal murine glucocorticoid, had potent dose-dependent effects on dendritic spine dynamics, increasing spine turnover within several hours in the developing barrel cortex. The adult barrel cortex exhibited diminished baseline spine turnover rates, but these rates were also enhanced by corticosterone. Similar changes occurred in multiple cortical areas, suggesting a generalized effect. However, reducing endogenous glucocorticoid activity by dexamethasone suppression or corticosteroid receptor antagonists caused a substantial reduction in spine turnover rates, and the former was reversed by corticosterone replacement. Notably, we found that chronic glucocorticoid excess led to an abnormal loss of stable spines that were established early in life. Together, these findings establish a critical role for glucocorticoids in the development and maintenance of dendritic spines in the living cortex.

Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior

A way to modulate reward-seeking Which brain regions are causally involved in reward-related behavior? Ferenczi et al. combined focal, cell type-specific, optogenetic manipulations with brain imaging, behavioral testing, and in vivo electrophysiology (see the Perspective by Robbins). Stimulation of midbrain dopamine neurons increased activity in a brain region called the striatum and was correlated with reward-seeking across individual animals. However, elevated excitability of an area called the medial prefrontal cortex reduced both striatal responses to the stimulation of dopamine neurons and the behavioral drive to seek the stimulation of dopamine neurons. Finally, modulating the excitability of medial prefrontal cortex pyramidal neurons drove changes in neural circuit synchrony, as well as corresponding anhedonic behavior. These observations resemble imaging and clinical phenotypes observed in human depression, addiction, and schizophrenia. Science, this issue p. 10.1126/science.aac9698; see also p. 10.1126/science.aad9698 Optogenetic and brain imaging approaches reveal a causal brainwide dynamical mechanism for the hedonic-anhedonic transition. [Also see Perspective by Robbins] INTRODUCTION The drive to seek and experience reward is conserved across species and, in mammals, involves interactions between subcortical dopaminergic systems and limbic structures such as the striatum. Impairment of this process, observed across a number of psychiatric conditions, is the clinical symptom of anhedonia (loss of enjoyment). The neural mechanisms underlying anhedonia are unknown but could result from abnormal interactions between cortical and subcortical reward circuits. We sought to test the hypothesis that elevated medial prefrontal cortex (mPFC) excitability (a clinical feature associated with anhedonia) exerts suppressive control over the interactions between two distant subcortical regions: the dopaminergic midbrain and the striatum. RATIONALE Clinical imaging studies have detected elevated activity in the mPFC in human patients with depression, and treatment is associated with normalization of this overactivity and improvement of anhedonic symptoms. Additionally, human studies have identified areas of the brain that respond to reward anticipation and experience, and this response can be suppressed in psychiatric disease. However, the source of this reward signal and the mechanisms underlying its modulation have not been causally demonstrated. We have integrated a diverse set of chronic and acute optogenetic tools with functional magnetic resonance imaging (fMRI) to provide a bridge between the causal, cellular specificity of rodent optogenetics and the brainwide observations that characterize human neuroimaging, with the goal of locally manipulating and globally visualizing neural activity to understand the regulation of reward-seeking behavior. RESULTS We demonstrate that stimulation of midbrain dopamine neurons drives both striatal fMRI blood oxygen level–dependent (BOLD) activity and reward-seeking behavior, and we show that these are correlated across individuals. We additionally find that silencing of dopamine neurons suppresses activity in the striatum, as well as in other brain regions (such as the hypothalamus), and drives avoidance behavior. Having established this bidirectional control of reward-seeking behavior, we then tested for perturbation of this circuitry via elevation of mPFC excitability. We observed suppression of striatal responses to dopamine, as well as the behavioral drive to seek out dopamine neuron stimulation and other natural rewarding stimuli. Finally, we demonstrate that stably elevated mPFC excitability synchronizes corticolimbic BOLD and electrophysiological activity, which in turn can predict anhedonic behavior in individual animals. CONCLUSION Our findings from experiments involving local cell-specific control, simultaneously with global unbiased observation of neural activity, reveal that the mPFC exerts top-down control over midbrain dopaminergic interactions with the striatum and that, when elevated, activity in the mPFC can suppress natural reward-related behavior. Furthermore, we observe that cortical-subcortical neural dynamics work in concert to regulate reward processing. All of these findings have implications for our understanding of natural reward-related physiology and behavior, as well as the pathogenesis of anhedonia. Reward-related signaling between the dopaminergic midbrain and the striatum is under suppressive control by the mPFC. Optogenetic fMRI was used to locally manipulate and globally visualize brainwide neural activity related to reward. Habituated rats were scanned in the awake state (top photographs). We establish that striatal BOLD activity is increased by optogenetic stimulation of dopamine neurons and decreased by optogenetic neural silencing. We demonstrate that focally elevated mPFC excitability suppresses reward-seeking behavior by exerting top-down control over striatal dopamine-induced activity and drives synchrony between specific corticolimbic circuits. Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.

Default Mode Network Mechanisms of Transcranial Magnetic Stimulation in Depression

BACKGROUND Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response. METHODS We used resting state functional magnetic resonance imaging to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a 5-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared with a cohort of 35 healthy control subjects. RESULTS Before treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. Transcranial magnetic stimulation normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. Transcranial magnetic stimulation also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement. CONCLUSIONS Transcranial magnetic stimulation selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response.

Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point?

Functional neuroimaging studies have identified multiple nodes of dysfunction in frontostriatal and mesocorticolimbic networks in attention-deficit/hyperactivity disorder (ADHD). Yet relatively few studies have examined how structural and functional connectivity between nodes in these networks might relate to the behavioral symptoms of ADHD. Moreover, it is unknown whether abnormalities in connectivity are a primary cause of symptoms or arise secondary to common etiologic mechanisms. We review the most recent diffusion tensor imaging and functional magnetic resonance imaging studies of connectivity in ADHD to characterize associations between frontostriatal connectivity abnormalities and the behavioral symptoms of inattention and impulsivity in ADHD. Furthermore, we examine how structural and functional connectivity measures relate to environmental and genetic pathways to ADHD. Diffusion tensor imaging studies indicate that ADHD is associated with significant irregularities in white matter microstructure, especially in frontostriatal and select corticocortical tracts. Resting state functional magnetic resonance imaging studies implicate altered connectivity within a default mode network of structures active during introspective, task-free processes and disrupted interactions between this network and frontostriatal attentional systems. Deficits in functional connectivity within frontostriatal and mesocorticolimbic networks might give rise, in part, to ADHD symptoms. Conversely, structural connectivity deficits and ADHD symptoms might arise incidentally from a common etiologic mechanism, involving altered modulation of synaptic potentiation and pruning by dopamine and other factors during development. Collectively, these studies suggest that the core symptoms of ADHD might derive from dysregulated modulation of cortical plasticity in the developing brain, resulting in altered patterns of corticocortical connectivity that might persist into adulthood.

Projections from neocortex mediate top-down control of memory retrieval.

Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC–CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC–CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC–CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations.