Arousal system stimulation and anesthetic state alter visuoparietal connectivity

Cortical information processing is under the precise control of the ascending arousal system (AAS). Anesthesia suppresses cortical arousal that can be mitigated by exogenous stimulation of the AAS. The question remains to what extent cortical information processing is regained by AAS stimulation. We investigate the effect of electrical stimulation of the nucleus Pontis Oralis (PnO), a distinct source of ascending AAS projections, on cortical functional connectivity (FC) and information storage at mild, moderate, and deep anesthesia. Local field potentials (LFPs) recorded previously in the secondary visual cortex (V2) and the adjacent parietal association cortex (PtA) in chronically instrumented unrestrained rats. We hypothesized that PnO stimulation would induce electrocortical arousal accompanied by enhanced FC and active information storage (AIS) implying improved information processing. In fact, stimulation reduced FC in slow oscillations (0.3–2.5 Hz) at low anesthetic level and increased FC at high anesthetic level. These effects were augmented following stimulation suggesting stimulus-induced plasticity. The observed opposite stimulation-anesthetic impact was less clear in the γ-band activity (30–70 Hz). In addition, FC in slow oscillations was more sensitive to stimulation and anesthetic level than FC in γ-band activity which exhibited a rather constant spatial FC structure that was symmetric between specific, topographically related sites in V2 and PtA. Invariant networks were defined as a set of strongly connected electrode channels, which were invariant to experimental conditions. In invariant networks, stimulation decreased AIS and increasing anesthetic level increased AIS. Conversely, in non-invariant (complement) networks, stimulation did not affect AIS at low anesthetic level but increased it at high anesthetic level. The results suggest that arousal stimulation alters cortical FC and information storage as a function of anesthetic level with a prolonged effect beyond the duration of stimulation. The findings help better understand how the arousal system may influence information processing in cortical networks at different levels of anesthesia

CHOLINERGIC CONTRIBUTIONS TO EMOTION REGULATION

Theories based on clinical and neuroanatomical studies implicate the muscarinic cholinergic system in normal and pathological emotion regulation. Emotional and sensory experiences can be induced with intravenous administration of the local anesthetic procaine hydrochloride, which selectively activates limbic regions in humans and animals. Procaine has a high affinity for muscarinic cholinergic receptors in vitro. This research tests three hypotheses: (1) procaine binds to muscarinic receptors in vivo; (2) procaine alters functional connectivity among cholinergic brain regions and their targets; and (3) procaine-induced emotions are related to core cholinergic regions. In Experiment I, anesthetized rhesus monkeys underwent positron emission tomography (PET) studies before and after administration of six doses of procaine on separate days using a radioligand with preferential binding to muscarinic M2 receptors ([18F]FP-TZTP). Procaine blocked [18F]FP-TZTP in a dose-response fashion uniformly across the brain, while significantly increasing tracer flow in limbic compared with non-limbic regions. In Experiment II, behavioral and physiological measures were assessed at baseline and following procaine in 32 healthy controls and 15 patients with bipolar disorder undergoing [15O] PET yielding regional cerebral blood flow (rCBF). Procaine selectively increased rCBF in anterior paralimbic regions in healthy controls, but to a lesser degree in patients. Regions connected via cholinergic pathways showed significantly different functional connectivity in both groups with procaine, however, prefrontal regions showed differential functional connectivity with cholinergic brain regions in patients compared with controls. Changes in activity of cholinergic regions explained the variance in anxiety ratings in an opposite manner in each group, and in euphoria ratings only in patients. In conclusion, procaine binds directly with muscarinic receptors in vivo while selectively increasing limbic activity in anesthetized monkeys. Two key findings herein procaine-induced alterations in functional connectivity of core cholinergic regions in humans, and the association of core cholinergic regional activity with emotional experience support theories implicating cholinergic contributions to emotion regulation. Decreased anterior paralimbic activity and altered functional connectivity of cholinergic regions in patients with bipolar illness compared with controls revealed by procaine offers additional insight into the regional neurobiology of the disease, and may ultimately be targeted in therapeutic approaches to bipolar disorder

Blast-Induced Tinnitus: A Combined Behavioral, Memri, And Electrophysiology Study

ABSTRACT BLAST-INDUCED TINNITUS: A COMBINED BEHAVIORAL, MEMRE, AND ELECTROPHYSIOLOGY STUDY by JESSICA OUYANG May 2014 Advisor: Drs. Steve Cala & Jinsheng Zhang Major: Physiology Degree: Doctor of Philosophy Tinnitus and hearing loss are the frequent auditory-related co-morbidities of blast trauma. The etiology of blast-induced tinnitus is also muddled by brain mechanisms associated with emotional and cognitive problems such as anxiety, memory loss, and depression. We set out to develop a realistic and ecologically valid model to address changes of cognitive status and psychological state that are associated with blast- induced tinnitus. In this study, 19 adult rats were randomly divided into the sham group (n=6) and the blast group (n=13). Blast exposure (14 psi) was conducted via a shock wave tube to expose the left ears of the rats in the blast group, and a sham exposure was conducted to the rats in the sham group. Blast-induced tinnitus was evaluated with gap detection and pre-pulse inhibition (PPI) acoustic startle reflex paradigms; the changes of thresholds of the hearing was evaluated with auditory brainstem response (ABRs), the change in the level of anxiety was evaluated with elevated plus maze; and the change in the status of memory was evaluated with one-day Morris water maze. To investigate blast-induced neuronal changes in the limbic structures, we utilized MEMRI technique. Obtained with MRIcro, MR intensity signal-to-noise ratios (SNRs) of 83 selected limbic structures were measured to represent the level of synaptic activity. Of the 13 rats that were exposed to blast shock wave, 8 rats developed chronic tinnitus on post-exposure day 35 (PED35) and 5 rats did not. Our results showed that compared to rats in the sham group (n=6), (1) rats in the blast group with or without tinnitus demonstrated higher level of anxiety (p\u3c0.05); (2) rats in the blast group that exhibited behavioral evidences of tinnitus (n=8) demonstrated neuronal hyperactivity in bilateral amygdaloidal complex, specifically bilateral basolateral groups and the left cortical-like group of the amygdala (p\u3c0.05); and (3) rats in the blast group demonstrated neuronal hyperactivity in bilateral nucleus accumbens core (p\u3c0.05). In conclusion, the elevated level of synaptic activity in the bilateral amygdala and nucleus accumbens core indicates central plasticity associated with blast-induced tinnitus

Restoring Consciousness During Seizures With Deep Brain Stimulation

Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy, and are refractory to all current medical and surgical therapies in about one sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the thalamic intralaminar central lateral nucleus (CL) and pontine nucleus oralis (PnO) bilaterally during focal limbic seizures restored normal-appearing cortical electrophysiology and markedly improved behavioral arousal. In contrast, single-site bilateral stimulation of CL or PnO alone was insufficient to achieve the same result. These findings support the ‘network inhibition hypothesis’ that focal limbic seizures impair consciousness through widespread inhibition of subcortical arousal. Driving subcortical arousal function would be a novel therapeutic approach to some forms of refractory epilepsy and may be compatible with devices already in use for responsive neurostimulation. Multi-site deep brain stimulation of subcortical arousal structures may benefit not only patients with epilepsy, but also other disorders of consciousness

Muscarinic attenuation of mnemonic rule representation in macaque dorsolateral prefrontal cortex during a pro- and anti-saccade task

Maintenance of context is necessary for execution of appropriate responses to diverse environmental stimuli. The dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in executive function, including working memory and representation of abstract rules, and is modulated by the ascending cholinergic system through nicotinic and muscarinic receptors. Muscarinic receptors’ effect on local primate DLPFC neural activity in vivo during cognitive tasks remains poorly understood. Here we examined the effects of muscarinic receptor blockade on rule-related activity in the macaque prefrontal cortex by combining iontophoretic application of the general muscarinic receptor antagonist scopolamine with single-unit recordings while monkeys performed a rule-guided saccade task. We found that scopolamine reduced overall neuronal firing rate and impaired rule discriminability of task-selective cells. Saccade and visual direction selectivity measures were also reduced by muscarinic antagonism. These results demonstrate that blockade of muscarinic receptors in dorsolateral prefrontal cortex creates deficits in working memory representation of rules in primates

The ACC is a critical hub for neuropathic pain- induced depression

Besides chronic stress, chronic pain is one of the prevalent determinants for depression. Indeed, around 50% of chronic pain patients develop mood disorders. Alterations in brain regions implicated in pain processing may also be involved in affective processing, thus potentially be responsible of mood disorders. However, the underlying mechanisms of this comorbidity are not yet elucidated. Here, we studied the role of the anterior cingulate cortex (ACC) in the somatosensory, aversive and anxiodepressive consequences of neuropathic pain. We showed that a permanent lesion or temporal inhibition of ACC pyramidal neurons blocked the development or suppressed the expression of an anxiodepressive phenotype in neuropathic mice. In addition, anxiodepressive-like behavior coincided with ACC hyperactivity. In conclusion we show that the ACC is a critical hub for neuropathic pain-induced depression

The Multi-Dimensional Contributions of Prefrontal Circuits to Emotion Regulation during Adulthood and Critical Stages of Development

The prefrontal cortex (PFC) plays a pivotal role in regulating our emotions. The importance of ventromedial regions in emotion regulation, including the ventral sector of the medial PFC, the medial sector of the orbital cortex and subgenual cingulate cortex, have been recognized for a long time. However, it is increasingly apparent that lateral and dorsal regions of the PFC, as well as neighbouring dorsal anterior cingulate cortex, also play a role. Defining the underlying psychological mechanisms by which these functionally distinct regions modulate emotions and the nature and extent of their interactions is a critical step towards better stratification of the symptoms of mood and anxiety disorders. It is also important to extend our understanding of these prefrontal circuits in development. Specifically, it is important to determine whether they exhibit differential sensitivity to perturbations by known risk factors such as stress and inflammation at distinct developmental epochs. This Special Issue brings together the most recent research in humans and other animals that addresses these important issues, and in doing so, highlights the value of the translational approach