Thalamocortical Feedback Loops Research Articles

Age-Related Changes in Sleep and Its Implications for Cognitive Decline in Aging Persons With Schizophrenia: A Critical Review.

Cognitive impairment is a core feature of schizophrenia that worsens with aging and interferes with quality of life. Recent work identifies sleep as an actionable target to alleviate cognitive deficits. Cardinal non-rapid eye movement (NREM) sleep oscillations such as sleep spindles and slow oscillations are critical for cognition. People living with schizophrenia (PLWS) and their first-degree relatives have a specific reduction in sleep spindles and an abnormality in their temporal coordination with slow oscillations that predict impaired memory consolidation. While NREM oscillatory activity is reduced in typical aging, it is not known how further disruption in these oscillations contributes to cognitive decline in older PLWS. Another understudied risk factor for cognitive deficits among older PLWS is obstructive sleep apnea (OSA) which may contribute to cognitive decline. We conducted a narrative review to examine the published literature on aging, OSA, and NREM sleep oscillations in PLWS. Spindles are propagated via thalamocortical feedback loops, and this circuitry shows abnormal hyperconnectivity in schizophrenia as revealed by structural and functional MRI studies. While the risk and severity of OSA increase with age, older PLWS are particularly vulnerable to OSA-related cognitive deficits because OSA is often underdiagnosed and undertreated, and OSA adds further damage to the circuitry that generates NREM sleep oscillations. We highlight the critical need to study NREM sleep in older PWLS and propose that identifying and treating OSA in older PLWS will provide an avenue to potentially mitigate and prevent cognitive decline.

Unilateral Optogenetic Inhibition and Excitation of Basal Ganglia Output Affect Directional Lick Choices and Movement Initiation in Mice

Models of basal ganglia (BG) function predict that tonic inhibitory output to motor thalamus (MT) suppresses unwanted movements, and that a decrease in such activity leads to action selection. Further, for unilateral activity changes in the BG, a lateralized effect on contralateral movements can be expected due to ipsilateral thalamocortical connectivity. However, a direct test of these outcomes of thalamic inhibition has not been performed. To conduct such a direct test, we utilized rapid optogenetic activation and inactivation of the GABAergic output of the substantia nigra pars reticulata (SNr) to MT in male and female mice that were trained in a sensory cued left/right licking task. Directional licking tasks have previously been shown to depend on a thalamocortical feedback loop between ventromedial MT and antero-lateral premotor cortex. In confirmation of model predictions, we found that unilateral optogenetic inhibition of GABAergic output from the SNr, during ipsilaterally cued trials, biased decision making towards a contralateral lick without affecting motor performance. In contrast, optogenetic excitation of SNr terminals in MT resulted in an opposite bias towards the ipsilateral direction confirming a bidirectional effect of tonic nigral output on directional decision making. However, direct optogenetic excitation of neurons in the SNr resulted in bilateral movement suppression, which is in agreement with previous results that show such suppression for nigral terminals in the superior colliculus (SC), which receives a bilateral projection from SNr.

Interaction between repetition suppression in motor activation and long-interval intracortical inhibition

Repetition suppression (RS) is the adaptation of the neural activity in response to a repeated external stimulus. It has been proposed that RS occurs at the thalamo-cortical level, hence activating a feedback loop to the cortex in order to counteract with the repeated motor cortical activation. In this study, to elucidate the common modulators between the RS and the inhibitory/facilitatory cortical networks, two TMS paradigms were applied, i.e. the characteristic long-interval intracortical inhibition (LICI) and the I1-wave timed short-interval intracortical facilitation (SICF). Since LICI is a local intracortical inhibitory phenomenon affecting cortical excitation over a long interval like the RS, the interaction between RS and LICI was tested. As the I1-wave timed SICF is likely not affected by inhibitory modulation, the appearance of the RS with respect to SICF was investigated. Non-linear interaction between LICI and RS was observed, while I1-wave timed SICF facilitated all MEP responses of RS by a common offset still preserving the RS. These findings implicate that the underlying mechanism for the observed interaction is likely contributed to the activation of the negative thalamo-cortical feedback loop represented by the RS, most likely at the cortical level.

A theory of consciousness: computation, algorithm, and neurobiological realization

The most enigmatic aspect of consciousness is the fact that it is felt, as a subjective sensation. The theory proposed here aims to explain this particular aspect. The theory encompasses both the computation that is presumably involved and the way in which that computation may be realized in the brain’s neurobiology. It is assumed that the brain makes an internal estimate of an individual’s own evolutionary fitness, which can be shown to produce a special, distinct form of causation. Communicating components of the fitness estimate (either for external or for internal use) requires inverting them. Such inversion can be performed by the thalamocortical feedback loop in the mammalian brain, if that loop is operating in a switched, dual-stage mode. A first (nonconscious) stage produces forward estimates, whereas the second (conscious) stage inverts those estimates. It is argued that inversion produces another special, distinct form of causation, which is spatially localized and is plausibly sensed as the feeling of consciousness.

P75-T Adaptation of the motor system is associated with neuroplasticity

Background Repetition suppression (RS), i.e., adaption of neural excitability in response to a repeated stimulus, manifests as a decrement in the amplitude of the motor evoked potentials (MEPs) following repeated transcranial magnetic stimulation (TMS) of the motor cortex. RS is associated with abnormal adaptation to external stimuli and may be indicative of neuroplastic capacity. Objective To investigate the association between RS and experimentally induced plasticity. Methods Fourteen healthy subjects (7 males, aged 22–42 years) were studied with a RS paradigm, which was applied prior and following (0 min, 10 min, and 20 min) paired associative stimulation (PAS). The RS paradigm, consisting of twenty trains of four TMS pulses with an inter-stimulus interval (ISI) of 1 s and an inter-train interval (ITI) of 17 s, was applied to abductor pollicis brevis muscle ‘hotspot’. During PAS, median nerve stimulation was delivered 25 ms prior to TMS pulses given at 0.2 Hz for 15 min. Results A two-way repeated ANOVA identified 6 subjects with an interaction effect of RS and PAS (p Conclusion Our results demonstrate that RS is facilitated in subjects showing the interaction effect. This interaction might be mediated by the GABAergic inhibitory system during activation of the negative thalamo-cortical feedback loop due to the homeostatic plasticity.

T232. Abnormal Thalamocortical Functional Connectivity Correlates With Sleep Spindle Deficits in Schizophrenia

A growing literature implicates abnormal thalamocortical circuitry in the pathophysiology of schizophrenia. Resting state functional connectivity MRI (rs-fcMRI) studies consistently report increased thalamic connectivity with sensorimotor cortex both in schizophrenia patients and in individuals at high risk, in whom it predicts conversion to psychosis. We examined the relation of thalamocortical functional connectivity to sleep spindles, defining EEG oscillations of non-rapid eye movement stage II sleep (N2) that are initiated in the thalamic reticular nucleus (TRN), depend on thalamocortical feedback loops for their expression and are reduced in schizophrenia.

Structural and functional connectivity between the lateral posterior-pulvinar complex and primary visual cortex in the ferret.

The role of higher-order thalamic structures in sensory processing remains poorly understood. Here, we used the ferret (Mustela putorius furo) as a novel model species for the study of the lateral posterior (LP)-pulvinar complex and its structural and functional connectivity with area 17 [primary visual cortex (V1)]. We found reciprocal anatomical connections between the lateral part of the LP nucleus of the LP-pulvinar complex (LPl) and V1. In order to investigate the role of this feedback loop between LPl and V1 in shaping network activity, we determined the functional interactions between LPl and the supragranular, granular and infragranular layers of V1 by recording multiunit activity and local field potentials. Coherence was strongest between LPl and the supragranular V1, with the most distinct peaks in the delta and alpha frequency bands. Inter-area interaction measured by spike-phase coupling identified the delta frequency band being dominated by the infragranular V1 and multiple frequency bands that were most pronounced in the supragranular V1. This inter-area coupling was differentially modulated by full-field synthetic and naturalistic visual stimulation. We also found that visual responses in LPl were distinct from those in V1 in terms of their reliability. Together, our data support a model of multiple communication channels between LPl and the layers of V1 that are enabled by oscillations in different frequency bands. This demonstration of anatomical and functional connectivity between LPl and V1 in ferrets provides a roadmap for studying the interaction dynamics during behaviour, and a template for identifying the activity dynamics of other thalamo-cortical feedback loops.

How the cortico-thalamic feedback affects the EEG power spectrum over frontal and occipital regions during propofol-induced sedation.

Increasing concentrations of the anaesthetic agent propofol initially induces sedation before achieving full general anaesthesia. During this state of anaesthesia, the observed specific changes in electroencephalographic (EEG) rhythms comprise increased activity in the δ- (0.5-4 Hz) and α- (8-13 Hz) frequency bands over the frontal region, but increased δ- and decreased α-activity over the occipital region. It is known that the cortex, the thalamus, and the thalamo-cortical feedback loop contribute to some degree to the propofol-induced changes in the EEG power spectrum. However the precise role of each structure to the dynamics of the EEG is unknown. In this paper we apply a thalamo-cortical neuronal population model to reproduce the power spectrum changes in EEG during propofol-induced anaesthesia sedation. The model reproduces the power spectrum features observed experimentally both in frontal and occipital electrodes. Moreover, a detailed analysis of the model indicates the importance of multiple resting states in brain activity. The work suggests that the α-activity originates from the cortico-thalamic relay interaction, whereas the emergence of δ-activity results from the full cortico-reticular-relay-cortical feedback loop with a prominent enforced thalamic reticular-relay interaction. This model suggests an important role for synaptic GABAergic receptors at relay neurons and, more generally, for the thalamus in the generation of both the δ- and the α- EEG patterns that are seen during propofol anaesthesia sedation.

P 110. Modifying sleep continuity parameters with tDCS

The regulation of sleep onset and maintenance is a complex process with a broad clinical significance. Several regulatory brain circuits have been identified, including an ascending reticular activating system and thalamo-cortical feedback loops ( Saper et al., 2005 ). Dysfunctions in one or more of those circuits might lead to an insomnia spectrum disorder. The “hyperarousal model of insomnia” ( Riemann et al., 2010 ) postulates an increased state of arousal leading to a disturbance of sleep onset and continuity. This arousal has been demonstrated in different systems, including cordial, metabolic and brain ( Riemann et al., 2010 ). Transcranial direct-current-stimulation (tDCS) has been shown having the potential to modify excitability in the prefrontal cortex and to modulate resting-state activity ( Keeser et al., 2011 ). The aim of this study is to answer the question whether modifying cortical excitability in the prefrontal cortex via bilateral tDCS leads to a change in excitability-dependent sleep parameters like sleep onset latency and the occurrence of arousal. The hypothesis is that prefrontal bidirectional anodal stimulation leads to an increase in excitability and arousal thereby disturbing sleep continuity whereas cathodal stimulation over the same region facilitates the opposite effect. Twenty-five patients with primary insomnia (as a human model for cortical hyperarousal) and twenty-five healthy subjects (16 females, aged 40–65 years) will be included after a thorough screening process. After adaptation to the sleep laboratory conditions, each participant will undergo a baseline polysomnography and three experimental sleep laboratory nights in intervals of 7 days with a tDCS protocol (two 10 min stimulation blocks with 20 min. inter-stimulation interval, bilateral frontal montage, parieto-occipital reference electrodes, intensity of current 1 mA over each electrode ( Monte-Silva et al., 2010 )) immediately prior to polysomnographically monitored sleep (11 pm to 7 am). Three different conditions (activation, deactivation, sham) will be applied in a counterbalanced order. Outcome parameters will include sleep latency, arousal parameters during NREM and REM sleep and EEG spectral parameters. Pilot data indicate changes in the wake EEG prior to sleep after prefrontal tDCS. First sleep results of the ongoing study will be presented at the conference. The results of this study are expected to improve our understanding of the impact of prefrontal cortical activity and arousal for the onset and maintenance of sleep. Results from this study might be informative for the development of novel treatments for sleep disruptions.

Anterior limb of the internal capsule in schizophrenia: a diffusion tensor tractography study

Thalamo-cortical feedback loops play a key role in the processing and coordination of processing and integration of perceptual inputs and outputs, and disruption in this connection has long been hypothesized to contribute significantly to neuropsychological disturbances in schizophrenia. To test this hypothesis, we applied diffusion tensor tractography to 18 patients suffering schizophrenia and 20 control subjects. Fractional anisotropy (FA) was evaluated in the bilateral anterior and posterior limbs of the internal capsule, and correlated with clinical and neurocognitive measures. Patients diagnosed with schizophrenia showed significantly reduced FA bilaterally in the anterior but not the posterior limb of the internal capsule, compared with healthy control subjects. Lower FA correlated with lower scores on tests of declarative episodic memory in the patient group only. These findings suggest that disruptions, bilaterally, in thalamo-cortical connections in schizophrenia may contribute to disease-related impairment in the coordination of mnemonic processes of encoding and retrieval that are vital for efficient learning of new information.

Stereotypical spatiotemporal activity patterns during slow-wave activity in the neocortex

Alternating epochs of activity and silence are a characteristic feature of neocortical networks during certain sleep cycles and deep states of anesthesia. The mechanism and functional role of these slow oscillations (<1 Hz) have not yet been fully characterized. Experimental and theoretical studies show that slow-wave oscillations can be generated autonomously by neocortical tissue but become more regular through a thalamo-cortical feedback loop. Evidence for a functional role of slow-wave activity comes from EEG recordings in humans during sleep, which show that activity travels as stereotypical waves over the entire brain, thought to play a role in memory consolidation. We used an animal model to investigate activity wave propagation on a smaller scale, namely within the rat somatosensory cortex. Signals from multiple extracellular microelectrodes in combination with one intracellular recording in the anesthetized animal in vivo were utilized to monitor the spreading of activity. We found that activity propagation in most animals showed a clear preferred direction, suggesting that it often originated from a similar location in the cortex. In addition, the breakdown of active states followed a similar pattern with slightly weaker direction preference but a clear correlation to the direction of activity spreading, supporting the notion of a wave-like phenomenon similar to that observed after strong sensory stimulation in sensory areas. Taken together, our findings support the idea that activity waves during slow-wave sleep do not occur spontaneously at random locations within the network, as was suggested previously, but follow preferred synaptic pathways on a small spatial scale.

Projections from bed nuclei of the stria terminalis, magnocellular nucleus: Implications for cerebral hemisphere regulation of micturition, defecation, and penile erection

The basic structural organization of axonal projections from the small but distinct magnocellular and ventral nuclei (of the bed nuclei of the stria terminalis) was analyzed with the Phaseolus vulgaris leucoagglutinin anterograde tract tracing method in adult male rats. The former's overall projection pattern is complex, with over 80 distinct terminal fields ipsilateral to injection sites. Innervated regions in the cerebral hemisphere and brainstem fall into nine general functional categories: cerebral nuclei, behavior control column, orofacial motor-related, humorosensory/thirst-related, brainstem autonomic control network, neuroendocrine, hypothalamic visceromotor pattern-generator network, thalamocortical feedback loops, and behavioral state control. The most novel findings indicate that the magnocellular nucleus projects to virtually all known major parts of the brain network that controls pelvic functions, including micturition, defecation, and penile erection, as well as to brain networks controlling nutrient and body water homeostasis. This and other evidence suggests that the magnocellular nucleus is part of a corticostriatopallidal differentiation modulating and coordinating pelvic functions with the maintenance of nutrient and body water homeostasis. Projections of the ventral nucleus are a subset of those generated by the magnocellular nucleus, with the obvious difference that the ventral nucleus does not project detectably to Barrington's nucleus, the subfornical organ, the median preoptic and parastrial nuclei, the neuroendocrine system, and midbrain orofacial motor-related regions.

Projections from bed nuclei of the stria terminalis, anteromedial area: Cerebral hemisphere integration of neuroendocrine, autonomic, and behavioral aspects of energy balance

The anteromedial area of the bed nuclei of the stria terminalis (BSTam) is the relatively undifferentiated region of the anterior medial (anteromedial) group of the bed nuclei of the stria terminalis (BSTamg), which also includes the more distinct dorsomedial, magnocellular, and ventral nuclei. The overall pattern of axonal projections from the rat BSTam was analyzed with the Phaseolus vulgaris-leucoagglutinin anterograde pathway tracing method. Brain areas receiving relatively moderate to strong inputs from the BSTam fall into five general categories: neuroendocrine system (regions containing pools of magnocellular oxytocin neurons, and parvicellular corticotropin-releasing hormone, thyrotropin-releasing hormone, somatostatin, and dopamine neurons); central autonomic control network (central amygdalar nucleus, descending paraventricular nucleus, and ventrolateral periaqueductal gray); hypothalamic visceromotor pattern generator network (five of six known components); behavior control column (descending paraventricular nucleus and associated arcuate nucleus; ventral tegmental area and associated nucleus accumbens and substantia innominata); and behavioral state control (supramammillary and tuberomammillary nuclei). The BSTam projects lightly to thalamocortical feedback loops (via the medial-midline-intralaminar thalamus). Its pattern of axonal projections, combined with its pattern of neural inputs (the most varied of all BST cell groups), suggests that the BSTam is part of a striatopallidal differentiation involved in coordinating neuroendocrine, autonomic, and behavioral or somatic responses associated with maintaining energy balance homeostasis.

Projections from bed nuclei of the stria terminalis, posterior division: Implications for cerebral hemisphere regulation of defensive and reproductive behaviors

The posterior division of the bed nuclei of the stria terminalis has three major nuclei: principal, interfascicular, and transverse, which receive topographically ordered inputs from the medial amygdalar nucleus. The overall pattern of axonal projections from each nucleus was determined in male rats with the Phaseolus vulgaris-leucoagglutinin method. Together, these nuclei project topographically back to the medial amygdalar nucleus, to the adjacent lateral septal nucleus, to the nucleus accumbens and substantia innominata, to hypothalamic parts of the behavior control column, and to the hypothalamic periventricular region, which controls patterned neuroendocrine and autonomic responses. The principal nucleus preferentially innervates septal and hypothalamic regions that control reproductive behavior and visceromotor responses, confirming a similar analysis by Gu et al. (J Comp Neurol [2003] 460:542-562). In contrast, the interfascicular and transverse nuclei differentially innervate septal and hypothalamic regions that control defensive as well as reproductive behaviors. In addition, the transverse nucleus projects significantly to midbrain parts of the behavior control column concerned with foraging/exploratory behavior. All three posterior division nuclei also project to thalamocortical feedback loops (by means of the nucleus reuniens and paraventricular nucleus). These structural data may be interpreted to suggest that the bed nuclei posterior division forms part (pallidal) of a corticostriatopallidal system involved in controlling two major classes of social (defensive and reproductive) behavior.

Organization of axonal projections from the anterolateral area of the bed nuclei of the stria terminalis.

The anterolateral group of the bed nuclei of the stria terminalis (BSTalg) contains four distinct cell groups embedded within an undifferentiated anterolateral area (BSTal) that architectonically resembles a subjacent subcommissural zone (BSTsc). The overall distributions of axonal projections from various regions of the BSTal and from the BSTsc were determined with the Phaseolus vulgaris-leucoagglutinin (PHAL) anterograde tracer method and found to be identical. The BSTal and BSTsc share dense bidirectional connections, and also project heavily within the BST to the rhomboid and fusiform nuclei and the anteroventral and anterodorsal areas. They project less densely to the juxtacapsular, oval, magnocellular, ventral, and interfascicular BST nuclei. Outside the BST, brain areas receiving strong to moderate inputs from the BSTal and BSTsc fall into several functional groups: somatomotor system (nucleus accumbens, substantia innominata, ventral tegmental area, and retrorubral area and adjacent midbrain reticular nucleus), central autonomic control system (central amygdalar nucleus, dorsal lateral hypothalamic area, ventrolateral periaqueductal gray, parabrachial nucleus, and nucleus of the solitary tract), neuroendocrine system (paraventricular and supraoptic nuclei, hypothalamic visceromotor pattern generator network), and thalamocortical feedback loops (midline, medial, and intralaminar nuclei). The results indicate that the BSTal and BSTsc are parts of the same cell group (dorsal and ventral to the anterior commissure), which plays a role in coordinating visceral and somatic motor responses (during ingestive behaviors, for example), especially in response to noxious stimuli (learned anorexia associated with noxious stimuli). BSTal projections are distinct from those of the adjacent juxtacapsular, oval, fusiform, and rhomboid nuclei.

Oscillatory corticothalamic response to somatosensory input

We construct a model of the thalamocortical feedback loop using the Random Neural Network model to provide a theoretical explanation for cortical and thalamic damped rapid (circa 60–100 Hz) oscillations which have been observed in lightly anesthesized rats with somatosensory input Nicolelis (1997). Experimental data corroborates the choice of model parameter settings. Model predictions indicate that positive feedback loops and large signaling delays within cortex significantly determine the oscillatory phenomenon and its duration (i.e. its decay), while positive feedback from cortex to thalamus is needed to exhibit oscillations in thalamus.

Driving of slow oscillations in the somatosensory system of the cat

Evoked potentials and neuronal activity, induced by repetitive stimulation of the sciatic nerve with brief electrical pulses, were recorded simultaneously from the surface and depth of the cerebral cortex and the specific and non-specific nublei of the thalamus, in cats under gallamine as well as in cats under barbiturates. Averaging and spectral analysis showed that the evoked potentials contained time locked components ranging in frequency from 0.5–6 c/sec and extending over periods as long as 3500 msec after the stimulus. When the frequency of stimulation was progressively increased from 0.25–6 pulses/sec it was found that the late oscillations could be “driven” at specific frequencies which caused an increase in the amplitudes of specific frequency components, harmonically related to each other and to the frequency of stimulation. The administration of barbiturates caused changes in the specific frequencies at which the late oscillations could be driven most effectively. These results are analogous to those obtained in the analysis of the late oscillations evoked in the human EEG by stimulation of the median nerve. Post stimulus histogram computed from the neuronal activity associated with the evoked potentials show that the peaks which indicate high levels of neuronal discharge, occur at intervals closely related to the period of the late oscillations. The time and phase relations between the late oscillations recorded from the cortex, the specific and the non specific thalamus, the time and phase relations between the discharge of different groups of neurons associated with them, and the fact that they can all be driven simultaneously at specific frequencies of stimulation, suggest that these phenomena are related to the driving, at resonant frequencies, of activities which develop in thalamic, cortical and thalamocortical feedback loops.