Thalamocortical Arousal Research Articles

Functional Connectivity of the Human Paraventricular Thalamic Nucleus: Insights From High Field Functional MRI.

The paraventricular thalamic nucleus (PVT) is a small but highly connected nucleus of the dorsal midline thalamus. The PVT has garnered recent attention as a context-sensitive node within the thalamocortical arousal system that modulates state-dependent motivated behaviors. Once considered related to generalized arousal responses with non-specific impacts on behavior, accumulating evidence bolsters the contemporary view that discrete midline thalamic subnuclei belong to specialized corticolimbic and corticostriatal circuits related to attention, emotions, and cognition. However, the functional connectivity patterns of the human PVT have yet to be mapped. Here, we combined high-quality, high-resolution 7T and 3T resting state MRI data from 121 young adult participants from the Human Connectome Project (HCP) and thalamic subnuclei atlas masks to investigate resting state functional connectivity of the human PVT. The 7T results demonstrated extensive positive functional connectivity with the brainstem, midbrain, ventral and dorsal medial prefrontal cortex (mPFC), anterior and posterior cingulate, ventral striatum, hippocampus, and amygdala. These connections persist upon controlling for functional connectivity of the rest of the thalamus. Whole-brain contrasts provided further evidence that, compared to three nearby midline thalamic subnuclei, functional connectivity of the PVT is strong with the hippocampus, amygdala, ventral and dorsal mPFC, and middle temporal gyrus. These findings suggest that, even during rest, the human PVT is functionally coupled with many regions known to be structurally connected to rodent and non-human primate PVT. Further, cosine similarity analysis results suggested the PVT is integrated into the default mode network (DMN), an intrinsic connectivity network associated with episodic memory and self-referential thought. The current work provides a much-needed foundation for ongoing and future work examining the functional roles of the PVT in humans.

Orexin-dependent activation of layer VIb enhances cortical network activity and integration of non-specific thalamocortical inputs.

Neocortical layer VI is critically involved in thalamocortical activity changes during the sleep/wake cycle. It receives dense projections from thalamic nuclei sensitive to the wake-promoting neuropeptides orexins, and its deepest part, layer VIb, is the only cortical lamina reactive to orexins. This convergence of wake-promoting inputs prompted us to investigate how layer VIb can modulate cortical arousal, using patch-clamp recordings and optogenetics in rat brain slices. We found that the majority of layer VIb neurons were excited by nicotinic agonists and orexin through the activation of nicotinic receptors containing α4-α5-β2 subunits and OX2 receptor, respectively. Specific effects of orexin on layer VIb neurons were potentiated by low nicotine concentrations and we used this paradigm to explore their intracortical projections. Co-application of nicotine and orexin increased the frequency of excitatory post-synaptic currents in the ipsilateral cortex, with maximal effect in infragranular layers and minimal effect in layer IV, as well as in the contralateral cortex. The ability of layer VIb to relay thalamocortical inputs was tested using photostimulation of channelrhodopsin-expressing fibers from the orexin-sensitive rhomboid nucleus in the parietal cortex. Photostimulation induced robust excitatory currents in layer VIa neurons that were not pre-synaptically modulated by orexin, but exhibited a delayed, orexin-dependent, component. Activation of layer VIb by orexin enhanced the reliability and spike-timing precision of layer VIa responses to rhomboid inputs. These results indicate that layer VIb acts as an orexin-gated excitatory feedforward loop that potentiates thalamocortical arousal.

Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy

The pedunculopontine (PPT) and laterodorsal (LDT) tegmental nuclei are involved in control of REM sleep and thalamocortical arousal. REM sleep behavior disorder (RBD) is a feature of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), which is also associated with visual hallucinations and cognitive fluctuations. We sought to determine the degree of PPT/LDT involvement in DLB compared to MSA. We counted the cholinergic neurons in the PPT and LDT in 13 patients with neuropathologically confirmed DLB, 11 patients with MSA, and 11 control cases. Five patients with DLB and eight patients with MSA had history or polysomnographic evidence of RBD. Ten patients with DLB and no patient with MSA had history of visual hallucinations or cognitive fluctuations. There was a significant loss of PPT and LDT neurons in both DLB and MSA. Cell loss in both the PPT and LDT was more severe in MSA than in DLB. The number of cells/section for the PPT were 148 +/- 21 in controls, 54 +/- 10 in DLB (p < 0.001), and 20 +/- 3 in MSA (p < 0.001), and for the LDT, 112 +/- 16 in controls, 49 +/- 8 in DLB (p < 0.01), and 16 +/- 2 in MSA (p < 0.001). Severity of neuronal loss in MSA or DLB did not relate to the presence or absence of history of RBD. Loss of cholinergic pedunculopontine tegmental nuclei/laterodorsal tegmental nuclei neurons occurs in both dementia with Lewy bodies and multiple system atrophy but is probably not the primary mechanism of REM sleep behavior disorder in these disorders.

Hypocretin and Nicotine Excite the Same Thalamocortical Synapses in Prefrontal Cortex: Correlation with Improved Attention in Rat

Thalamic projections to prefrontal cortex are important for executive aspects of attention. Using two-photon imaging in prefrontal brain slices, we show that nicotine and the wakefulness neuropeptide hypocretin (orexin) excite the same identified synapses of the thalamocortical arousal pathway within the prefrontal cortex. Although it is known that attention can be improved when nicotine is infused directly into the midlayer of the prefrontal cortex in the rat, the effects of hypocretin on attention are not known. The overlap in thalamocortical synapses excited by hypocretin and nicotine and the lack of direct postsynaptic effects prompted us to compare their effects on a sustained and divided attention task in the rat. Similar to nicotine, infusions of hypocretin-2 peptide into the prefrontal cortex significantly improved accuracy under high attentional demand without effects on other performance measures. We show for the first time that hypocretin can improve attentional processes relevant to executive functions of the prefrontal cortex.

How brain arousal systems determine different temperament types and the major dimensions of personality

Theory and research is described which led to the hypothesis that the choleric (E+N+) and melancholic (E−N+) temperaments are determined by differences in thalamocortical inhibition of brain-stem processes. An opportunity to test this hypothesis was provided by the recent discovery of 4, 7, and 10 Hz response waves confounded in EEG averaged evoked potentials [Robinson, D. L. (1999b). The technical, neurological, and psychological significance of ‘alpha’ ‘theta’ and ‘delta’ waves confounded in EEG evoked potentials: 1. A study of peak latencies. Electroencephalography and Clinical Neurophysiology , 110 , 1427–1434; (2000). The technical neurological, and psychological significance of ‘alpha’, ‘delta’, and ‘theta’ waves confounded in EEG evoked potentials: A study of peak amplitudes. Personality and Individual Differences, 28 , 673–693]. These responses are attributed to the brain-stem, limbic, and thalamocortical arousal systems, respectively, and in the cited reports principal components analysis of data obtained from 93 participants confirmed the existence of predicted excitatory and inhibitory relationships. ANOVA was used in the present study to test the further prediction that there should be strong inhibition of the 4 Hz system by the 10 Hz system in melancholics (E−N+) and weak inhibition of the 4 Hz system in cholerics (E+N+), with median inhibition predicted for the other temperament types. There was a large and statistically significant difference between the mean scores on the PCA inhibition factor obtained for the temperament groups, with temperament defined in terms of high and low EPQ extraversion (E) and neuroticism (N) scores. The significance of these results is discussed with reference to fundamental questions raised by Pavlov's pioneering research but left unanswered for the best part of a century. Implications for the future conduct of personality research are also considered.

SPECT during sleepwalking

Sleepwalking is a dissociation between body sleep and mind sleep. We report single photon emission computed tomography (SPECT) in a man with a history of sleepwalking. Our findings suggest that this dissociation arises from activation of thalamocingulate pathways and persisting deactivation of other thalamocortical arousal systems.

Opposite patterns of P300 asymmetry in schizophrenia are syndrome related

In schizophrenia reduction of the P300 amplitude is a robust statistical finding but with inconsistent evidence of symptom correlates and of lateral asymmetry. Here relations were examined with active and withdrawn syndromes which in other cognitive and electrophysiological measurement modalities have been associated with opposite functional asymmetries. A standard oddball detection task was used to elicit auditory evoked potentials from dextral DSM-IV schizophrenic patients. On clinical ratings blind to the psychophysiology, eight were classified as withdrawn and 12 had a predominance of active syndrome features. Both patient groups had congruent P300 maxima at Pz or P4, attesting to their application to the detection task. Syndromes were differentiated by opposite asymmetries in P300, N200–P300 and N100 amplitudes at the posterior temporal sites: a reduction in P300 and N200–P300 amplitudes on the left in the active patients, and a reduction on the right in the withdrawn patients, with the opposite asymmetries in N100 amplitudes. The syndrome-related asymmetries in P300, also manifested in earlier attentional (N100) components are interpreted in terms of thalamo-cortical arousal systems having generalised, internalised influences, rather than in terms of later cognitive processes underpinning the P300. The findings endorse a syndromal approach to laterality research in schizophrenia.

Contributions of the pedunculopontine region to normal and altered REM sleep.

The pedunculopontine (PPN) region of the upper brainstem is recognized as a critical modulator of activated behavioral states such as wakefulness and rapid eye movement (REM) sleep. The expression of REM sleep-related physiology (e.g. thalamocortical arousal, ponto-geniculate-occipital (PGO) waves, and atonia) depends upon a subpopulation of PPN neurons that release acetylcholine (ACh) to act upon muscarinic receptors (mAChRs). Serotonin's potent hyperpolarization of cholinergic PPN neurons is central to present working models of REM sleep control. A growing body of experimental evidence and clinical experience suggests that the responsiveness of the PPN region, and thereby modulation of REM sleep, involves closely adjacent glutamatergic neurons and alternate afferent neurotransmitters. Although many of these afferents are yet to be defined, dopamine-sensitive GABAergic pathways exiting the main output nuclei of the basal ganglia and adjacent forebrain nuclei appear to be the most conspicuous and the most likely to be clinically relevant. These GABAergic pathways are ideally sited to modulate the physiologic hallmarks of REM sleep differentially (e.g. atonia versus cortical activation), because each originates from a functionally unique forebrain circuit and terminates in a unique pattern upon brain stem neurons with unique membrane characteristics. Evidence is reviewed that changes in the quality, timing, and quantity of REM sleep that characterize narcolepsy, REM sleep behavior disorder, and neurodegenerative and affective disorders (depression and schizophrenia) reflect 1) changes in responsiveness of cells in the PPN region governed by these afferents; 2) increase or decrease in PPN cell number; or 3) mAChRs mediating increased responsiveness to ACh derived from the PPN. Auditory evoked potentials and acoustic startle responses provide means independent from recording sleep to assess pathophysiologies affecting the PPN and its connections and thereby complement investigations of their role in affecting daytime functions (e.g. arousal and attention).

Chronic nimodipine and acute metrifonate treatment decreases age-related cortical high voltage spindles in rats.

We studied the effect of nimodipine (1000 ppm mixed in food), an L-type calcium-channel antagonist, administered for 4 months, on the cortical EEG activity in young and aged rats. Nimodipine treatment decreased cortical high voltage spindles (HVSs) in aged rats, but did not prevent the diminution of spontaneous locomotor activity. The threshold dose of metrifonate, a cholinesterase inhibitor, for suppression of HVSs was lower in nimodipine compared to placebo treated aged rats (30 mg/kg versus 60 mg/kg; p.o.). In young rats, nimodipine did not decrease HVSs, protect from scopolamine (0.1 or 0.8 mg/kg, i.p.) induced EEG slowing or augment the effect of metrifonate to suppress slow waves induced by scopolamine. The present results suggest that a chronic nimodipine treatment modulates thalamocortical arousal and thereby adds to the therapeutic effects of metrifonate to restore normal cortical electrical arousal in aged rats.

Symmetric Bithalamic and Striatal Hemorrhage Following Perinatal Hypoxia in a Term Infant

A full-term infant who demonstrated a prolonged period of obtundation following asphyxia at birth was found on cranial computed tomography (CT) to have hemorrhage limited exclusively to symmetric bithalamic and striatal areas. This pattern of discrete, symmetric nuclear hemorrhage has not so far been reported as a complication of birth asphyxia. It differs from the germinal matrix hemorrhage on one hand in having a later time of onset (between the 4th and 10th day of life). It is also distinct from the more common supratentorial parenchymal hemorrhages in full-term infants owing to its topography, consequent interruption of the thalamocortical arousal mechanisms, and prolonged period of obtundation.

Interrelationship among multiunit activity of the midbrain reticular formation and lateral geniculate nucleus, thalamocortical arousal, and behavior in rats.

Analyses of multiunit activity of midbrain reticular formation (RF) and lateral geniculate nucleus (LG) revealed marked phasic covariation that conformed to characteristics of behavior. Movement patterns appeared to set the range within which RF activity and thalamocortical arousal (as reflected in LG activity) varied. In tests of spontaneous behavior, sensory stimulation, bar pressing for food, and conditioned emotional response. RF activity and thalamocortical arousal conformed to immediate properties of behavior apart from conditions giving rise to the behavior. Other analyses revealed close relationships between RF activity and visual evoked response, but only a general relationship to hippocampal slow-wave rhythms. Our findings emphasize the necessity for refining psychological conceptualizations of arousal processes.