Aberrant brain dynamics in individuals with clinical high risk of psychosis.

Background: Resting-state network (RSN) functional connectivity analyses have profoundly influenced our understanding of the pathophysiology of psychoses and their clinical high risk (CHR) states. However, conventional RSN analyses address the static nature of large-scale brain networks. In contrast, novel methodological approaches aim to assess the momentum state and temporal dynamics of brain network interactions. Methods: Fifty CHR individuals and 33 healthy controls (HC) completed a resting-state functional MRI scan. We performed an Energy Landscape analysis, a data-driven method using the pairwise maximum entropy model, to describe large-scale brain network dynamics such as duration and frequency of, and transition between, different brain states. We compared those measures between CHR and HC, and examined the association between neuropsychological measures and neural dynamics in CHR. Results: Our main finding is a significantly increased duration, frequency, and higher transition rates to an infrequent brain state with coactivation of the salience, limbic, default mode and somatomotor RSNs in CHR as compared to HC. Transition of brain dynamics from this brain state was significantly correlated with processing speed in CHR. Conclusion: In CHR, temporal brain dynamics are attracted to an infrequent brain state, reflecting more frequent and longer occurrence of aberrant interactions of default mode, salience, and limbic networks. Concurrently, more frequent and longer occurrence of the brain state is associated with core cognitive dysfunctions, predictors of future onset of full-blown psychosis.

Reduced anterior callosal white matter in risk for psychosis associated with processing speed as a fundamental cognitive impairment.

BACKGROUND: Previous research in psychotic disorders discovered associations between reduced integrity of white matter (WM) in the corpus callosum (CC) and impaired cognitive functions, suggesting processing speed as a central construct. However, it is still largely unexplored to what extent disruption in callosal WM is related to cognitive deficits during the risk stage prior to psychosis. METHODS: To address this gap, we measured the WM integrity in CC by fractional anisotropy (FA) and assessed cognition in 60 clinical-high risk for psychosis (CHR) patients during adolescence/young adulthood and 38 healthy control (HC) subjects. We employed tract based spatial statistics to examine group differences and associations between CC-FA and processing speed, executive function, and spatial working memory. RESULTS: We revealed deficits in processing speed, executive function, and spatial working memory of CHR patients, and reductions in FA of the genu and the body of the CC (p < 0.05, corrected for multiple comparisons) compared to HC. A mediation analysis using the combined sample (CHR + HC) showed that processing speed mediates the associations between the impaired CC structure and executive function and spatial working memory, respectively. Exploratory analyses between CC-FA and the cognitive domains located associations of processing speed in the genu and the body of CC with distinct spatial distributions of executive function and spatial working memory. CONCLUSION: We suggest processing speed as a subordinate cognitive factor contributing to the associations between callosal WM, executive function and working memory. These results extend findings in psychotic disorders to the prior risk stage.

Ventral pallidum regulates the default mode network, controlling transitions between internally and externally guided behavior.

Daily life requires transitions between performance of well-practiced, automatized behaviors reliant upon internalized representations and behaviors requiring external focus. Such transitions involve differential activation of the default mode network (DMN), a group of brain areas associated with inward focus. We asked how optogenetic modulation of the ventral pallidum (VP), a subcortical DMN node, impacts task switching between internally to externally guided lever-pressing behavior in the rat. Excitation of the VP dramatically compromised acquisition of an auditory discrimination task, trapping animals in a DMN state of automatized internally focused behavior and impairing their ability to direct attention to external sensory stimuli. VP inhibition, on the other hand, facilitated task acquisition, expediting escape from the DMN brain state, thereby allowing rats to incorporate the contingency changes associated with the auditory stimuli. We suggest that VP, instant by instant, regulates the DMN and plays a deterministic role in transitions between internally and externally guided behaviors.

Aspects of tree shrew consolidated sleep structure resemble human sleep.

Understanding human sleep requires appropriate animal models. Sleep has been extensively studied in rodents, although rodent sleep differs substantially from human sleep. Here we investigate sleep in tree shrews, small diurnal mammals phylogenetically close to primates, and compare it to sleep in rats and humans using electrophysiological recordings from frontal cortex of each species. Tree shrews exhibited consolidated sleep, with a sleep bout duration parameter, τ, uncharacteristically high for a small mammal, and differing substantially from the sleep of rodents that is often punctuated by wakefulness. Two NREM sleep stages were observed in tree shrews: NREM, characterized by high delta waves and spindles, and an intermediate stage (IS-NREM) occurring on NREM to REM transitions and consisting of intermediate delta waves with concomitant theta-alpha activity. While IS-NREM activity was reliable in tree shrews, we could also detect it in human EEG data, on a subset of transitions. Finally, coupling events between sleep spindles and slow waves clustered near the beginning of the sleep period in tree shrews, paralleling humans, whereas they were more evenly distributed in rats. Our results suggest considerable homology of sleep structure between humans and tree shrews despite the large difference in body mass between these species.

Basal forebrain contributes to default mode network regulation.

The default mode network (DMN) is a collection of cortical brain regions that is active during states of rest or quiet wakefulness in humans and other mammalian species. A pertinent characteristic of the DMN is a suppression of local field potential gamma activity during cognitive task performance as well as during engagement with external sensory stimuli. Conversely, gamma activity is elevated in the DMN during rest. Here, we document that the rat basal forebrain (BF) exhibits the same pattern of responses, namely pronounced gamma oscillations during quiet wakefulness in the home cage and suppression of this activity during active exploration of an unfamiliar environment. We show that gamma oscillations are localized to the BF and that gamma-band activity in the BF has a directional influence on a hub of the rat DMN, the anterior cingulate cortex, during DMN-dominated brain states. The BF is well known as an ascending, activating, neuromodulatory system involved in wake-sleep regulation, memory formation, and regulation of sensory information processing. Our findings suggest a hitherto undocumented role of the BF as a subcortical node of the DMN, which we speculate may be important for switching between internally and externally directed brain states. We discuss potential BF projection circuits that could underlie its role in DMN regulation and highlight that certain BF nuclei may provide potential target regions for up- or down-regulation of DMN activity that might prove useful for treatment of DMN dysfunction in conditions such as epilepsy or major depressive disorder.

Gamma band directional interactions between basal forebrain and visual cortex during wake and sleep states.

The basal forebrain (BF) is an important regulator of cortical excitability and responsivity to sensory stimuli, and plays a major role in wake-sleep regulation. While the impact of BF on cortical EEG or LFP signals has been extensively documented, surprisingly little is known about LFP activity within BF. Based on bilateral recordings from rats in their home cage, we describe endogenous LFP oscillations in the BF during quiet wakefulness, rapid eye movement (REM) and slow wave sleep (SWS) states. Using coherence and Granger causality methods, we characterize directional influences between BF and visual cortex (VC) during each of these states. We observed pronounced BF gamma activity particularly during wakefulness, as well as to a lesser extent during SWS and REM. During wakefulness, this BF gamma activity exerted a directional influence on VC that was associated with cortical excitation. During SWS but not REM, there was also a robust directional gamma band influence of BF on VC. In all three states, directional influence in the gamma band was only present in BF to VC direction and tended to be regulated specifically within each brain hemisphere. Locality of gamma band LFPs to the BF was confirmed by demonstration of phase locking of local spiking activity to the gamma cycle. We report novel aspects of endogenous BF LFP oscillations and their relationship to cortical LFP signals during sleep and wakefulness. We link our findings to known aspects of GABAergic BF networks that likely underlie gamma band LFP activations, and show that the Granger causality analyses can faithfully recapitulate many known attributes of these networks.