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Large-Scale Neuroimaging and Genetic Analyses of the Human Thalamus in Loneliness.

BACKGROUND: Although loneliness is prevalent and significantly impacts society globally, its neural and genetic bases remain poorly understood. The thalamus, which receives sensory information from the environment, may have a more significant role in social interactions than previously recognized. Here, we integrate neuroimaging and genetic approaches to characterize structural differences within the thalamus associated with loneliness. METHODS: We obtained thalamic nuclei volumes on brain scans from 45,834 individuals (age range: 45-82 years) in the UK Biobank and grouped them into 6 anatomical groups. We investigated effects of loneliness and social isolation using self-reported data. Then, we performed a genome-wide association study (GWAS) analysis on the genetic overlap between thalamic volumes and loneliness. RESULTS: The volumes of the whole thalamus and its medial, lateral, and posterior nuclei are significantly reduced in individuals with loneliness compared with those who do not feel lonely. Loneliness with frequent social contact is associated with smaller volumes, whereas social isolation without loneliness shows no such reduction in thalamus volumes. Leveraging data from GWASs on thalamic volumes (n = 30,114) and loneliness (n = 370,342) in the UK Biobank, we identified shared loci between thalamus structure and loneliness. CONCLUSIONS: Our findings support the emerging view that the thalamus plays important roles in social interactions and in the experience of loneliness.

Genetic architecture

The cingulate bridge between allocortex, isocortex and thalamus.

The Fink-Heimer silver impregnation and the autoradiographic methods were used to study the fiber projections of the cingulate cortex in the squirrel monkey. It was found that this cortex provides inputs to the straitum, thalamus and several areas of isocortex. Evidence was found for a number of fiber projections (1) Fibers from the anterior limbic area were traced to the central part of the head of the caudate nucleus, putamen, septum, dorsomedial nucleus of the thalamus, anterior hypothalamus and lateral basal nucleus of the amygdala. (2) Projections from the cingulate area were traced to the lateral part of the head of the caudate nucleus, putamen, and to the centromedian, anterior, lateral dorsal, and lateral ventral thalamic nuclei and to medial nuclei of the base of the pons. (3) There were porjections from the retrosplenial area of the anterior, lateral dorsal, dorsomedial, and posterior thalamic nuclei and lateral nuclei of the pons. These results indicate that most of the cingulate gyrus is an intermediate structure between the thalamus and overlying cortex. The anterior limbic area forms a bridge between the thalamus and other areas of the cingulate gyrus and the frontal cortex. (4) the retrosplenial area and the posterior part of the cingulate area bridge the adjacent visual snesory association cortex and pelvic areas of the snesory motor cortex, respectively. These areas of the cingulate gyrus project directly to the striatum as well as to the thalamus, structurally providing limbic system input to subcortical motor structures.

Animals

Evidence for a GABAergic projection from the substantia nigra to the ventromedial thalamus and to the superior colliculus of the rat.

Unilateral intranigral infusion of kainic acid (1.5 microgram) produced neuronal loss in the lateral two-thirds of the nigra while sparing axons en passage. Fink-Heimer silver impregnation revealed dense terminal degeneration in the nigra itself (both in the compacta and in the reticulata) and in areas of non-dopaminergic nigral projection such as the ventromedial (VM) nucleus of the thalamus, the superior colliculus and the reticular formation; only spare terminal degeneration was found in areas of dopaminergic projection such as the caudate and septum. In order to clarify the nature of the transmitter of the nigrothalamic and nigrocollicular neurons, the activity of glutamic decarboxylase (GAD), the marker of cholinergic neurons, was measured in the VM and ventrobasal (VB) thalamus and in the nigra of each side, 7 days after unilateral intranigral injection of kainic acid. GAD activity was reduced significantly in the VM-thalamus (-33%), in the superior colliculus (-40%) and in the substantia nigra (-18%) but not in the VB-thalamus of the lesioned side. CAT remained unchanged in these areas. Similar results were obtained in the thalamus and in the superior colliculus after electrocoagulative lesions of the nigra. The results indicate the existence of a nigrothalamic and of a nigrocollicular GABAergic pathway. This projection might play an important role in motor coordination and gaze control.

Animals

Vestibular-related neuronal activity in the thalamus of the alert monkey during sinusoidal rotation in the dark.

1. In the alert monkey neuronal activity was recorded in the ventro-posterior nucleus (VP) of the thalamus in the dark during sinusoidal rotation over a frequency range from 0.01-1 Hz. 2. From 57 neurons 38 (67%) were activated with rotation to the ipsilateral side (type I) and 19 (33%) to the contralateral side (type II). The spontaneous activity was low (average 10.1 imp/sec) and irregular. No activity changes were found with eye movements. 3. At 0.2-0.1 Hz neuronal activity showed a phase lead of 10-20 degrees relative to chair velocity. At the lowest frequency (0.01 Hz) the phase lead was only slightly higher (about 30 degrees). Accordingly the decrease in gain was only moderate. 4. At lower frequencies the simultaneously recorded eye movements (nystagmus) showed an increase in phase lead comparable to the values for the neuronal activity in the thalamus. For both neuronal activity in the thalamus and nystagmus a time constant between 25-35 sec was calculated. 5. The data are compared with vestibular nerve and nuclei recordings. It is argued that the time constants of vestibular neurons in the thalamus are very similar to the time constants of neurons in the vestibular nuclei in alert animals.

Animals

Types of neuronal responses in the rat thalamus to peripheral temperature changes.

Recordings were made of spike-trains from 163 neurons of the rostral part of the ventrobasal thalamus complex of the rat while the temperature of the scrotal skin was altered. The following results were obtained: 55 neurons were non-thermosensitive, 7 neurons cold-sensitive and 101 neurons warm-sensitive. In the case of the warm-sensitive cells a definite discrimination was possible: 61.4% of the neurons altered their firing behavior during peripheral cooling, changing from relatively even spike frequency to burst firing. This change could be induced repeatedly by altering the temperature. 38.6% of the neurons, on the other hand, reacted to cooling by slowing down their frequency. By way of statistical methods the firing patterns of the two response-types were analyzed more precisely and the differences in response to temperature stimuli more exactly defined. Likewise, the spatial distribution of the two response-types of warm-sensitive cells exhibited differences; whereas the cells devoid of burst activity occured rather uniformly in the region of the thalamus studied, the cells with bursting activity were confined more to the mediocaudal region. These findings are discussed with regard to the phenomenon of peripheral bursts and to the projection of thermoafferent pathways onto the ventrobasal thalamus complex. The functional interpretation of the various cell reactions and their role in the central processing of thermoafferent signals still remains unexplained and requires comparative studies of peripheral and central parts of the thermoafferent system.

Animals

Subcellular localization of monoamine oxidase in bovine thalamus tissue using immunoferritin conjugates.

A combination of discontinuous sucrose gradient analysis and polyacrylamide electrophoresis was used to isolate one of the multiple forms of monoamine oxidase (MAO) from bovine thalamus. This substance (the principle form and the most anodic of the five MAO forms observed) was used as a basis for an immunoferritin-electron microscope approach to determine the subcellular localization of MAO in thalamus. This form of MAO, as well as antigenically related forms, was found to reside mainly on the outer mitochondrial membrane. In addition, the action of SDS on solubilization and interconversion of MAO forms was studied and found to be dependent on the concentration and time of reaction of SDS with thalamus tissue.

Animals

An autoradiographic study of the projections of the pretectum in the rhesus monkey (Macaca mulatta): evidence for sensorimotor links to the thalamus and oculomotor nuclei.

Autordiographic tracing methods were used to determine the differential projections of the pretectal nuclei, in the rhesus monkey, in relation to their inputs. The sublentiform (SL) and olivary (ON) nuclei receive projections from the visual cortex, superior colliculus (SC) and equal bilateral projection from the retina. The nucleus of the posterior commissure (NPC) and its subdivisions do not receive any of these inputs. The projections of the pretectum involve a number of structures within the thalamus and brain stem and there are differences in the projection targets of the pretectal region which receives direct visual input (i.e., SL and ON) and the region which does not (i.e., nucleus of the posterior commissure, NPC). For example, while all pretectal regions project within the pretectum and to the SC, accessory oculomotor nuclei, reticular formation, intralaminar nuclei and hypothalamus, it is only the retinorecipient zone which projects to rostral regions such as the visceral oculomotor nuclei, the lateral pulvinar, the border between the lateral pulvinar and medial pulvinar, the oral pulvinar as well as to the thalamic reticular nucleus, ventral lateral geniculate nucleus, zona incerta and other structures. It is concluded that the retina, SC and cortex which influence the visceral oculomotor nuclei can only do so by virtue of their projections to the pretectum, and that any consideration of accommodative and pupillary reflexes must view the pretectum as an obligatory link through which various structures can influence the intrinsic musculature of the eye. In contrast to the SC, the pretectum does not project to any of the visual relay nuclei of the thalamus, such as the inferior pulvinar, which project to the visual cortices. Instead, the pretectum projects directly to visuomotor, visceromotor and arousal systems.

Animals

Stimulation of the thalamus and its effect on electrographic manifestations of the brain in unrestrained rats.

The thalamus was electrically stimulated in unrestrained rats with implanted cortical and subcortical electrodes. Single pulses often triggered rhythmic cortical activity identical with the 8--9/sec spike episodes which occur spontaneously in rats in the walking state. In rhythmic stimulation of the thalamus, self-sustained 3/sec spike-wave paroxysmal activity, with partial clonic jerks, was observed. Specific and non-specific thalamic nuclei participated in the production of these activities.

Animals

The relationship between vigilance and cortical EEG manifestations after electrical stimulation of the thalamus and hippocampus in unrestrained rats.

The thalamus or hippocampus of unanaesthetized rats with impaired cortical and subcortical electrodes was stimulated with rhythmic series of electrical pulses of 3--15/sec frequency. In both cases, stimulation either did not affect vigilance, or led to a higher degree of wakefulness. The incidence of recruiting responses (RR) and of self-sustained afterdischarges (SSAD) evoked by stimulation of the thalamus was not correlated to the preceding state of vigilance. In stimulation of the hippocampus, a significantly higher incidence of SSAD was found in the quiet waking state. The correlation between the elicitation of RR and SSAD was also significantly the highest after stimulation of the hippocampus during wakefulness.

Animals

Quantitative comparison of the hominoid thalamus. I. Specific sensory relay nuclei.

Studies to date have indicated few differences in sensory perception among hominoids. Sensory relay nuclei in the dorsal thalamus--portions of the medial and lateral geniculate bodies (MGBp, LGBd) and the ventrobasal complex (VB)--in two gibbons, one gorilla, one chimpanzee and three humans were examined for anatomical similarity by measuring and estimating the nuclear volumes, neuronal densities, numbers of neurons per nucleus, and volumes of neuronal perikarya. The absolute volumes of these nuclei were larger in the larger brains; however, with the volume of the dorsal thalamus as a standard, these sensory relay nuclei showed negative allometry. The gibbons had about half as many neurons as did the other hominoids. Although the human VB had slightly more neurons, the numbers of neurons in LGBd and MGBp did not significantly differ between the great apes and humans. The volumetric distribution of the neuronal perikarya were similar among these hominoids. Other thalamic nuclei had much more diverse numbers of neurons and relative frequencies of their neuronal perikarya. The sensory relay nuclei appear to be a group of conservative nuclei in the forebrain. These results suggest that as a neurological base for complex behaviors evolved in hominids, not all parts of the brain changed equally.

Animals

[Relationship between a state of sleep and wakefulness and transmission of an afferent signal through the posterior ventral nucleus of the thalamus].

Chronic experiments were carried out on nonanesthetized cats. A study was made of peculiarities attending the transmission of the afferent signals and the following inhibitory processes in the posterior ventral nucleus of the thalamus, depending on the state of sleep and wakefulness. Transmission of the signals decreases during the dreaming condition and the slow-wave sleep, and increases during the active states of alert cats. In paradoxical sleep the signal transmission is at the same level as such at resting wakeful condition. A marked transmission fluctuation is seen during the dreaming state and in the course of the first phase of sleep. The level of signal transmission is the most stable during the active states. The degree of the trance inhibitory process after the afferent signal transmission depends on the level of anesthesia, wakefulness and natural sleep. Processes following the afferent signal transmission in the posterior ventral nucleus of the thalamus show a radical difference in the barbituiate-anesthetized in comparison with nonanesthetized animals. The trace inhibition, so characteristic of anesthesia, was expressed in the dreaming state of the animal but insignificantly; in the wakeful condition it is not manifested at all.

Anesthesia, General

An autoradiographic study of the projections of visual cortical area 1 to the thalamus, pretectum and superior colliculus of the rabbit.

The projections of visual cortical area 1 (vl) to the thalamus, pretectum and superior colliculus of the rabbit have been studied by Giolli and Guthrie ('67, '71) using the Nauta and Fink-Heimer methods to determine the course and distribution of degenerating nerve fibers. The present study represents a reinvestigation of these same projections utilizing the tracing method of autoradiography. An injection of 3H leucine was produced within a small region of vl in each of 18 adult albino rabbits, and the brains were subsequently processed for autoradiography by the method of Cowan et al. ('72). The results have confirmed the observations of Giolli and Guthrie ('67, '71) (1) by showing that vl of the rabbit projects to the thalamic reticular nucleus, the ventral lateral geniculate nucleus, the dorsal lateral geniculate nucleus; the pulvinar, the anterior and posterior pretectal nuclei and the superior colliculus and (2) by showing that a particular retinotopic organization is present in each of these projections. However, unlike Giolli and Guthrie ('67, '71), the present autoradiographic study has further revealed (1) that both the ventrolateral and the posterior thalamic nuclei receive inputs from vl and (2) that the nucleus of the optic tract is not innervated by axons originating from vl.

Animals

Adrenergic modulation of a cholinergic emotional reaction in the cat's thalamus.

Direct carbachol stimulation of the intralaminar nuclei of the thalamus evokes an affective defense reaction in the cat. Pretreatment of the region with noradrenaline inhibited the reaction in a dose-related manner. Phenylephrine was ineffective in this respect while isoprenaline exhibited roughly the same inhibitory action as noradrenaline. The alpha-receptor blocking dihydroergotamine left the inhibitory effect of noradrenaline unaffected while the beta-receptor blocking propranolol abolished it. These findings suggest that the inhibitory effect of noradrenaline on the carbachol-induced thalamic emotional reaction is caused by its influence on beta-type adrenergic receptors. Since a similar adrenergic-cholinergic interaction was previously demonstrated also for the hypothalamus and red nucleus, it can be concluded that adrenergic modulation of cholinergic reactions in the central nervous sytem seems to be a principle of more general validity than has been assumed thus far.

Animals

A peculiar rhythmic EEG activity from ventrobasal thalamus during paradoxical sleep in man.

A peculiar 3/sec rhythmic EEG activity (named Vc rhythm) was consistently found at the ventrobasal thalamus (nucleus ventrocaudalis) during paradoxical sleep of patients with implanted electrodes used as an electrophysiological procedure for identification of the thalamic targets for the surgical treatment of tremor and rigidity. The Vc rhythm was formed by high voltage, sharp biphasic positive negative potentials which were absent during wakefulness, rare and isolated during slow wave sleep, increased in number and organized in trains during paradoxical sleep and blocked during arousal. Significant changes in number of Vc waves were found when patients shifted through these wakefulness-sleep states. Integrated EMG multiple unit activity also showed significant changes during these wakefulness-sleep shifts, which were parallel although inverse to those showed by Vc waves. A significant negative correlation (r = -0.7126) between number of Vc waves and EMG units was found. In contrast, Vc waves showed no correlation with other electrophysiological indicators of thalamic excitability (multiple unit activity and early evoked potentials) and sleep (scalp EEG frequency and ocular movements).

Electric Stimulation

Synaptic vesicle fraction devoid of adenosine triphosphatase activity from bovine caudatolenticular nuclei and thalamus.

1. As a part of studies on the mechanism by which catecholamines are released from the nerve terminals, the synaptic vesicle fraction was isolated from bovine caudatolenticular nuclei and thalamus by differential centrifugation essentially according to the method of Kadota and Kadota (17). 2. Further centrifugation on a sucrose density gradient of the synaptic vesicle fraction by the method of Whittaker et al. (1) yielded white materials on the upper portion of 0.4 M sucrose, which consisted of vesicles averaging 600-800 A in diameter, and did not show Mg2+-dependent ATpase activity. On the other hand, the denser materials centering on 0.6 M sucrose, consisting of a mixture of microsomes and synaptic vesicles of 400-500 A diameter, showed an ATpase activity activated by either Mg2+ or Ca2+ but not inhibited by ouabain. 3. The white materials on 0.4 M sucrose were almost free of mitochondria, but they contained a large amount of non-heme iron, as reported elsewhere (2). Furthermore, the protein components analyzed on SDS-polyacrylamide gels were similar to those already reported for purified synaptic vesicles (3). 4. Based on these results, the white materials were assumed to be synaptic vesicles devoid of Mg2+-dependent ATPase activity.

Adenosine Triphosphatases

A specific pattern of connections from the sensorimotor region of the cerebral cortex to the thalamus in the rat.

In the course of an investigation of the thalamic connections of the frontoparietal cortex in the albino rat, lesions were placed in the parietal cortex of adult rats, and the resulting terminal degeneration was observed in the ventrobasal complex, using the Fink-Heimer silver impregnation technique. Lesions made in the primary somatosensory forelimb region of the cortex result in a narrow band of terminal degeneration which extends dorsoventrally throughout the rostrocaudal two-thirds of the ventrobasal complex. This portion of the ventrobasal complex coincides with the electrophysiological representation of the thalamic primary somatosensory forelimb area, and corresponds closely to the medial portion of the lateral part of the ventrobasal complex as described by Smith, as well as to the medial portion of the posterolateral ventral nucleus according to Matano et al. These results serve to confirm the close correlation determined electrophysiologically between the topographical organization of the somatosensory forelimb areas of both the parietal cortex and the ventrobasal complex of the rat thalamus.

Animals

Neuropathology of Huntington's chorea. Studies of the ventrobasal complex of the thalamus.

In seven cases of Huntington's chorea, the ventrolateral thalamus was studied by quantitative cytometry. A selective 50 percent atrophy of microneurons (internuncial cells) was found while the macroneurons did not show significant atrophy. Thalamic microneurons might be presynaptic and postsynaptic inhibitory cells. Their specific atrophy in Huntington's chorea thus could be related to the known decrease of gamma aminobutyric acid (GABA) in Huntington's chorea.

Adult

Relations between the pulvinar-lateralis posterior complex of the thalamus and the hippocampus in wakefulness and sleep in cats.

Paucisynaptic connections between n. lateralis posterior (LP) and dorsal hippocampus (Hip) have been demonstrated in acute experiments. In the free moving cats, with chronic implanted electrodes on the neocortex, in LP, pulvinar (Pul), VA and VL nuclei of the thalamus and in the dorsal hippocampus (Hip), the theta waves recorded in LP, Pul and Hip were not of the same frequency and origin. In wakefulness and in slow-wave sleep, the theta waves were of 3.5-4 c/s and occurred exclusively or predominantly in Pul-LP, while in paradoxical sleep they were of 5-6 c/s, occurred' in Hip and invaded the Pul-LP. These two types of theta waves represent two distinct modalities of their organization and reflect the involvement of different mechanisms in the different phases of sleep.

Animals