Intralaminar Nuclei Research Articles

The Upper Ascending Reticular Activating System between Intralaminar Thalamic Nuclei and Cerebral Cortex in the Human Brain

Purpose: The ascending reticular activating system (ARAS) is responsible for regulation of consciousness. In this study, using diffusion tensor imaging (DTI), we attempted to reconstruct the thalamocortical projections between the intralaminar thalamic nuclei and the frontoparietal cortex in normal subjects. Methods: DTI data were acquired in 24 healthy subjects and eight kinds of thalamocortical projections were reconstructed: the seed re gion of interest (ROI) - the intralaminar thalamic nuclei and the eight target ROIs - the medial prefrontal cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, premotor cortex, primary motor cortex, primary somatosensory cortex, and posterior parietal cortex. Results: The eight thalamocortical projections were reconstructed in each hemisphere and the pathways were visualized: projections to the prefrontal cortex ascended through the anterior limb and genu of the internal capsule and anterior corona radiata. Projections to the premotor cortex passed through the genu and posterior limb of the internal capsule and middle corona radiata; in contrast, projections to the primary motor cortex, primary somatosensory cortex, and posterior parietal cortex ascended through the posterior limb of the in ternal capsule. No significant difference in fractional anisotropy, mean diffusivity, and fiber volume of all reconstructed thalamocortical projections was observed between the right and left hemispheres (p>0.05). Conclusion: We reconstructed the thalamocortical projections between the intralaminar thalamic nuclei and the frontoparietal cortex in normal subjects. We believe that our findings would be useful to clinicians involved in the care of patients with impaired consciousness and for researchers in studies of the ARAS.

The immunohistochemical distribution of the GABAA receptor α1, α2, α3, β2/3 and γ2 subunits in the human thalamus

The GABAA receptor is the most abundant inhibitory receptor in the human brain and is assembled from a variety of different subunit subtypes which determines their pharmacology and physiology. To determine which GABAA receptor subunit proteins are found in the human thalamus we investigated the distribution of five major GABAA receptor subunits α1, α2, α3, β2,3 and γ2 using immunohistochemical techniques. The α1-, β2,3- and γ2- subunits which combine to form a benzodiazepine sensitive GABAA receptor showed the most intense levels of staining and were the most common subunits found throughout the human thalamus especially in the ventral and posterior nuclear groups. The next most intense staining was for the α3-subunit followed by the α2-subunit. The intralaminar nuclear group, the mediodorsal nucleus and the thalamic reticular nucleus contained α1-, β2,3- and γ2- subunits staining as well as the highest levels of the α2- and α3- subunits. The sensory dorsal lateral geniculate nucleus contained very high levels of α1- and β2,3- and γ2-subunits. The highest densities of GABAA receptors found throughout the thalamus which contained the subunits α1, β2,3, and γ2 included nuclei which are especially involved in the control or the modulation of the cortico-basal ganglia-thalamo-cortical motor circuits and are thus important in disorders such as Huntington's disease where the GABAergic projections of the basal ganglia are compromised. In addition the majority of receptors in the thalamic reticular nucleus contain α3 and γ2 subunits whilst the intralaminar nuclei contain high levels of α2 and α3 subunits.

Environmental enrichment enhances systems-level consolidation of a spatial memory after lesions of the ventral midline thalamus

Lesions of the reuniens and rhomboid (ReRh) thalamic nuclei in rats do not alter spatial learning but shorten the period of memory persistence (Loureiro et al. 2012). Such persistence requires a hippocampo-cortical (prefrontal) dialog leading to memory consolidation at the systems level. Evidence for reciprocal connections with the hippocampus and the medial prefrontal cortex (mPFC) makes the ReRh a potential hub for regulating hippocampo-cortical interactions. As environmental enrichment (EE) fosters recovery of declarative-like memory functions after diencephalic lesions (e.g., anterior thalamus), we studied the possibility of triggering recovery of systems-level consolidation in ReRh lesioned rats using a 40-day postsurgical EE. Remote memory was tested 25days post-acquisition in a Morris water maze. The functional activity associated with retrieval was quantified using c-Fos imaging in the dorsal hippocampus, mPFC, intralaminar thalamic nuclei, and amygdala. EE enhanced remote memory in ReRh rats. Conversely, ReRh rats housed in standard conditions were impaired. C-Fos immunohistochemistry showed a higher recruitment of the mPFC in enriched vs. standard rats with ReRh lesions during retrieval. ReRh rats raised in standard conditions showed weaker c-Fos expression than their sham-operated counterparts. The reinstatement of memory capacity implicated an EE-triggered modification of functional connectivity: EE reduced a marked lesion-induced increase in baseline c-Fos expression in the amygdala. Thus, enriched housing conditions counteracted the negative impact of ReRh lesions on spatial memory persistence. These effects could be the EE-triggered consequence of an enhanced neuronal activation in the mPFC, along with an attenuation of a lesion-induced hyperactivity in the amygdala.

Parafascicular thalamic nucleus deep brain stimulation decreases NMDA receptor GluN1 subunit gene expression in the prefrontal cortex

The rodent parafascicular nucleus (PFn) or the centromedian-parafascicular complex of primates is a posterior intralaminar nucleus of the thalamus related to cortical activation and maintenance of states of consciousness underlying attention, learning and memory. Deep brain stimulation (DBS) of the PFn has been proved to restore arousal and consciousness in humans and to enhance performance in learning and memory tasks in rats. The primary expected effect of PFn DBS is to induce plastic changes in target neurons of brain areas associated with cognitive function. In this study, Wistar rats were stimulated for 20mins in the PFn following a DBS protocol that had previously facilitated memory in rats. NMDA and GABAB receptor binding, and gene expression of the GluN1subunit of the NMDA receptor (NMDAR) were assessed in regions related to cognitive functions, such as the prefrontal cortex and hippocampus. The results showed that PFn DBS induced a decrease in NMDAR GluN1 subunit gene expression in the cingulate and prelimbic cortices, but no significant statistical differences were found in the density of NMDA or GABAB receptors in any of the analyzed regions. Taken together, our findings suggest a possible role for the NMDAR GluN1 subunit in the prefrontal cortex in the procognitive actions of the PFn DBS.

Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults

In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.

Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons.

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

Functional properties of nociceptive neurons in the nucleus centralis lateralis of the cat thalamus.

We studied functional properties of nociceptive neurons in the thalamic intralaminar nuclei, especially the nucleus centralis lateralis (CL) in urethane-chloralose anesthetized cats. Nociceptive neurons were found in the intralaminar nuclei, i.e. CL, nucleus centralis medialis (CeM) and nucleus parafascicularis (Pf). One third of these nociceptive neurons had their receptive fields throughout the body, including the orofacial area. Namely, they received convergent nociceptive input from the trigeminal and spinal nerve territories. These neurons with widely complex receptive fields were similar to those we found in the middle third of the caudal bulbar reticular formation (RF). Electrical stimulation of the CL antidromically activated about half of the caudal bulbar RF neurons tested. Furthermore, electrical stimulation of the cingulate gyrus antidromically activated some of CL neurons. These findings suggest that most of the CL neurons receiving nociceptive input from throughout the body receive information directly or indirectly via the caudal bulbar RF, and that certain of this information is then conveyed to the cingulate gyrus.

Differential effects of systemic morphine on responses elicited by tooth pulp stimulation of nociceptive neurons in lateral and medial thalamic nuclei.

The effects of intravenous morphine on responses of feline thalamic nociceptive neurons receiving afferent input from the tooth pulp (TP) were investigated. Morphine suppressed responses to TP stimulation in both tooth pulp specific (TPS) and wide dynamic range (WDR) neurons with TP input recorded from the nucleus ventralis posteromedialis (VPM). However, there was scant morphine effect on responses to stimulation of trigeminothalamic tract (TTT) fibers in the trigeminal medial lemniscus. Furthermore, in nociceptive neurons with TP input recorded from nucleus centralis lateralis (CL) and parafascicularis (Pf) of the intralaminar nuclei, intravenous morphine suppressed responses both to stimulation of the mesencephalic reticular formation (MRF) as well as TP stimulation. The suppressive action of morphine on responses elicited by TP stimulation of VPM, CL and Pf neurons was antagonized by intravenous naloxone (1 mg/kg). Results suggest that intravenous morphine suppresses synaptic transmission of nociceptive impulses in the intralaminar nuclei as well as in the lower brain stem but not in the VPM.

Intralaminar and tectal projections to the subthalamus in the rat.

Projections from the posterior intralaminar thalamic nuclei and the superior colliculus (SC) to the subthalamic nucleus (STN) and the zona incerta (ZI) have been described in the primate and rodent. The aims of this study was to investigate several questions on these projections, using modern neurotracing techniques in rats, to advance our understanding of the role of STN and ZI. We examined whether projection patterns to the subthlamus can be used to identify homologues of the primate centromedian (CM) and the parafascicular nucleus (Pf) in the rodent, the topography of the projection including what percent of intralaminar neurons participate in the projections, and electron microscopic examination of intralaminar synaptic boutons in STN. The aim on the SC‐subthalamic projection was to examine whether STN is the main target of the projection. This study revealed: (i) the areas similar to primate CM and Pf could be recognized in the rat; (ii) the Pf‐like area sends a very heavy topographically organized projection to STN but very sparse projection to ZI, which suggested that Pf might control basal ganglia function through STN; (iii) the projection from the CM‐like area to the subthalamus was very sparse; (iv) Pf boutons and randomly sampled asymmetrical synapses had similar distributions on the dendrites of STN neurons; and (v) the lateral part of the deep layers of SC sends a very heavy projection to ZI and moderate to sparse projection to limited parts of STN, suggesting that SC is involved in a limited control of basal ganglia function.

Multimodal 7T Imaging of Thalamic Nuclei for Preclinical Deep Brain Stimulation Applications.

Precise neurosurgical targeting of electrode arrays within the brain is essential to the successful treatment of a range of brain disorders with deep brain stimulation (DBS) therapy. Here, we describe a set of computational tools to generate in vivo, subject-specific atlases of individual thalamic nuclei thus improving the ability to visualize thalamic targets for preclinical DBS applications on a subject-specific basis. A sequential nonlinear atlas warping technique and a Bayesian estimation technique for probabilistic crossing fiber tractography were applied to high field (7T) susceptibility-weighted and diffusion-weighted imaging, respectively, in seven rhesus macaques. Image contrast, including contrast within thalamus from the susceptibility-weighted images, informed the atlas warping process and guided the seed point placement for fiber tractography. The susceptibility-weighted imaging resulted in relative hyperintensity of the intralaminar nuclei and relative hypointensity in the medial dorsal nucleus, pulvinar, and the medial/ventral border of the ventral posterior nuclei, providing context to demarcate borders of the ventral nuclei of thalamus, which are often targeted for DBS applications. Additionally, ascending fiber tractography of the medial lemniscus, superior cerebellar peduncle, and pallidofugal pathways into thalamus provided structural demarcation of the ventral nuclei of thalamus. The thalamic substructure boundaries were validated through in vivo electrophysiological recordings and post-mortem blockface tissue sectioning. Together, these imaging tools for visualizing and segmenting thalamus have the potential to improve the neurosurgical targeting of DBS implants and enhance the selection of stimulation settings through more accurate computational models of DBS.

Participation of the thalamic CM-Pf complex in movement performance in patients with dystonia.

The centrum medianum- parafascicular complex of the human thalamus has a critical influence on cortical activity and significantly influences somatosensory function, arousal, and attention. In addition to its cortical connections, this region of the intralaminar thalamic nuclei is also connected to motor areas of the basal ganglia and the brain stem. The goal of this study was to identify movement-related neurons in the centrum medianum-parafascicular complex and analyze the changes in their activity during voluntary movements in patients with cervical dystonia. Single-unit activity was recorded during the micro-electrode-guided surgical ablation procedures in patients with cervical dystonia. The neural responses and synchronous electromyographic signals of the neck and finger flexor muscles were simultaneously recorded. We found the following 3 types of movement-sensitive neurons in the centrum medianum-parafascicular complex: neurons that responded selectively to voluntary hand movement (hand-only neurons), neurons that selectively responded to neck movements (neck-only neurons), neurons responding to both hand and neck movements (combined neurons). We discovered the following 3 patterns of movement-related changes in neural activity: an increase in the firing rate, a reduction in the bursting activity, and short-term oscillations and synchronization with neighboring neurons. The most pronounced and prolonged responses were observed during movements involving neck muscles as well as during involuntary dystonic movements. The centrum medianum-parafascicular complex of the thalamus is a component of the subcortical network that participates in motor behavior and may be involved in the pathophysiology of cervical dystonia. © 2016 International Parkinson and Movement Disorder Society.

Rostral Intralaminar Thalamic Deep Brain Stimulation Triggered Cortical and Hippocampal Structural Plasticity and Enhanced Spatial Memory

Background/Aims: Rostral intralaminar thalamic nucleus (ILN) has been shown to modulate cognition through indirect connection with the hippocampus and prefrontal cortex. We explored the effects of deep brain stimulation (DBS) to the rostral ILN on spatial memory acquisition, brain neuronal activation and cortical and hippocampal synaptic changes in rats. Methods: The Morris water maze (MWM) task was used to evaluate the spatial memory of the rats. The expression of c-fos, an immediate early gene, was used to identify neural activation in the cerebral cortex and hippocampus. Synaptic changes in the somatosensory cortical and hippocampal neurons were explored with dendritic spine analysis following Golgi-Cox staining. Results: Our results showed that a barrage of DBS to the rostral ILN of normal rats significantly shortened their escape latency in MWM compared with sham-stimulated and untreated control rats. Rats with enhanced spatial memory had more c-fos immunoreactive cells in layer IV of the somatosensory cortex. Layer III cortical and CA1 hippocampal pyramidal neurons showed over 50% increase of dendritic spines, while only the proximal apical dendrites of layer V cortical pyramidal neurons had more dendritic spines. Conclusions: Rostral ILN-DBS activated neurons in the cerebral cortex and triggered cortical and hippocampal structural plasticity in association with spatial memory enhancement.

Neural correlates of the mother-to-infant social transmission of fear.

Although clinical and basic studies show that parental trauma, fear, and anxiety may be transmitted to offspring, the neurobiology of this transmission is still not well understood. We recently demonstrated in an animal model that infant rats acquire threat responses to a distinct cue when a mother expresses fear to this cue in their presence. This ability to acquire maternal fear through social learning is present at birth and, as we previously reported, depends on the pup's amygdala. However, the remaining neural mechanisms underlying social fear learning (SFL) in infancy remain elusive. Here, by using [(14) C]2-deoxyglucose autoradiography, we show that the mother-to-infant transmission of fear in preweaning rats is associated with a significant increase of activity in the subregions of the lateral septum, nucleus accumbens, bed nucleus of stria terminalis, retrosplenial cortex, paraventricular nucleus of the thalamus, mediodorsal and intralaminar thalamic nuclei, medial and the lateral preoptic nuclei of the hypothalamus, and the lateral periaqueductal gray. In contrast to studies of adult SFL demonstrating the role of the anterior cingulate cortex and possibly the insular cortex or research of infant classical fear conditioning showing the role of the posterior piriform cortex, no changes of activation in these areas were observed. Our results indicate that the pup's exposure to maternal fear activates a number of areas involved in processing threat, stress, or pain. This pattern of activation suggests a unique set of neural mechanisms underlying SFL in the developing brain.

Basal ganglia and cerebellar interconnectivity within the human thalamus

Basal ganglia and the cerebellum are part of a densely interconnected network. While both subcortical structures process information in basically segregated loops that primarily interact in the neocortex, direct subcortical interaction has been recently confirmed by neuroanatomical studies using viral transneuronal tracers in non-human primate brains. The thalamus is thought to be the main relay station of both projection systems. Yet, our understanding of subcortical basal ganglia and cerebellar interconnectivity within the human thalamus is rather sparse, primarily due to limitation in the acquisition of in vivo tracing. Consequently, we strive to characterize projections of both systems and their potential overlap within the human thalamus by diffusion MRI and tractography. Our analysis revealed a decreasing anterior-to-posterior gradient for pallido-thalamic connections in: (1) the ventral-anterior thalamus, (2) the intralaminar nuclei, and (3) midline regions. Conversely, we found a decreasing posterior-to-anterior gradient for dentato-thalamic projections predominantly in: (1) the ventral-lateral and posterior nucleus; (2) dorsal parts of the intralaminar nuclei and the subparafascicular nucleus, and (3) the medioventral and lateral mediodorsal nucleus. A considerable overlap of connectivity pattern was apparent in intralaminar nuclei and midline regions. Notably, pallidal and cerebellar projections were both hemispherically lateralized to the left thalamus. While strikingly consistent with findings from transneuronal studies in non-human primates as well as with pre-existing anatomical studies on developmentally expressed markers or pathological human brains, our assessment provides distinctive connectional fingerprints that illustrate the anatomical substrate of integrated functional networks between basal ganglia and the cerebellum. Thereby, our findings furnish useful implications for cerebellar contributions to the clinical symptomatology of movement disorders.

Combined Optogenetic and Freeze-fracture Replica Immunolabeling to Examine Input-specific Arrangement of Glutamate Receptors in the Mouse Amygdala

Freeze-fracture electron microscopy has been a major technique in ultrastructural research for over 40 years. However, the lack of effective means to study the molecular composition of membranes produced a significant decline in its use. Recently, there has been a major revival in freeze-fracture electron microscopy thanks to the development of effective ways to reveal integral membrane proteins by immunogold labeling. One of these methods is known as detergent-solubilized Freeze-fracture Replica Immunolabeling (FRIL). The combination of the FRIL technique with optogenetics allows a correlated analysis of the structural and functional properties of central synapses. Using this approach it is possible to identify and characterize both pre- and postsynaptic neurons by their respective expression of a tagged channelrhodopsin and specific molecular markers. The distinctive appearance of the postsynaptic membrane specialization of glutamatergic synapses further allows, upon labeling of ionotropic glutamate receptors, to quantify and analyze the intrasynaptic distribution of these receptors. Here, we give a step-by-step description of the procedures required to prepare paired replicas and how to immunolabel them. We will also discuss the caveats and limitations of the FRIL technique, in particular those associated with potential sampling biases. The high reproducibility and versatility of the FRIL technique, when combined with optogenetics, offers a very powerful approach for the characterization of different aspects of synaptic transmission at identified neuronal microcircuits in the brain. Here, we provide an example how this approach was used to gain insights into structure-function relationships of excitatory synapses at neurons of the intercalated cell masses of the mouse amygdala. In particular, we have investigated the expression of ionotropic glutamate receptors at identified inputs originated from the thalamic posterior intralaminar and medial geniculate nuclei. These synapses were shown to relay sensory information relevant for fear learning and to undergo plastic changes upon fear conditioning.

Combined Optogenetic and Freeze-fracture Replica Immunolabeling to Examine Input-specific Arrangement of Glutamate Receptors in the Mouse Amygdala.

Freeze-fracture electron microscopy has been a major technique in ultrastructural research for over 40 years. However, the lack of effective means to study the molecular composition of membranes produced a significant decline in its use. Recently, there has been a major revival in freeze-fracture electron microscopy thanks to the development of effective ways to reveal integral membrane proteins by immunogold labeling. One of these methods is known as detergent-solubilized Freeze-fracture Replica Immunolabeling (FRIL).The combination of the FRIL technique with optogenetics allows a correlated analysis of the structural and functional properties of central synapses. Using this approach it is possible to identify and characterize both pre- and postsynaptic neurons by their respective expression of a tagged channelrhodopsin and specific molecular markers. The distinctive appearance of the postsynaptic membrane specialization of glutamatergic synapses further allows, upon labeling of ionotropic glutamate receptors, to quantify and analyze the intrasynaptic distribution of these receptors. Here, we give a step-by-step description of the procedures required to prepare paired replicas and how to immunolabel them. We will also discuss the caveats and limitations of the FRIL technique, in particular those associated with potential sampling biases. The high reproducibility and versatility of the FRIL technique, when combined with optogenetics, offers a very powerful approach for the characterization of different aspects of synaptic transmission at identified neuronal microcircuits in the brain.Here, we provide an example how this approach was used to gain insights into structure-function relationships of excitatory synapses at neurons of the intercalated cell masses of the mouse amygdala. In particular, we have investigated the expression of ionotropic glutamate receptors at identified inputs originated from the thalamic posterior intralaminar and medial geniculate nuclei. These synapses were shown to relay sensory information relevant for fear learning and to undergo plastic changes upon fear conditioning.

Organization of the sleep-related neural systems in the brain of the river hippopotamus (Hippopotamus amphibius): A most unusual cetartiodactyl species.

This study provides the first systematic analysis of the nuclear organization of the neural systems related to sleep and wake in the basal forebrain, diencephalon, midbrain, and pons of the river hippopotamus, one of the closest extant terrestrial relatives of the cetaceans. All nuclei involved in sleep regulation and control found in other mammals, including cetaceans, were present in the river hippopotamus, with no specific nuclei being absent, but novel features of the cholinergic system, including novel nuclei, were present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic, and orexinergic systems and is extended to the γ-aminobutyric acid (GABA)ergic elements of these nuclei. Quantitative analysis reveals that the numbers of pontine cholinergic (259,578) and noradrenergic (127,752) neurons, and hypothalamic orexinergic neurons (68,398) are markedly higher than in other large-brained mammals. These features, along with novel cholinergic nuclei in the intralaminar nuclei of the dorsal thalamus and the ventral tegmental area of the midbrain, as well as a major expansion of the hypothalamic cholinergic nuclei and a large laterodorsal tegmental nucleus of the pons that has both parvocellular and magnocellular cholinergic neurons, indicates an unusual sleep phenomenology for the hippopotamus. Our observations indicate that the hippopotamus is likely to be a bihemispheric sleeper that expresses REM sleep. The novel features of the cholinergic system suggest the presence of an undescribed sleep state in the hippopotamus, as well as the possibility that this animal could, more rapidly than other mammals, switch cortical electroencephalographic activity from one state to another. J. Comp. Neurol. 524:2036-2058, 2016. © 2016 Wiley Periodicals, Inc.

Inflammatory cytokines influence measures of white matter integrity in bipolar disorder

Midcingulate cortex (MCC) has risen in prominence as human imaging identifies unique structural and functional activity therein and this is the first review of its structure, connections, functions and disease vulnerabilities. The MCC has two divisions (anterior, aMCC and posterior, pMCC) that represent functional units and the cytoarchitecture, connections and neurocytology of each is shown with immunohistochemistry and receptor binding. The MCC is not a division of anterior cingulate cortex (ACC) and the “dorsal ACC” designation is a misnomer as it incorrectly implies that MCC is a division of ACC. Interpretation of findings among species and developing models of human diseases requires detailed comparative studies which is shown here for five species with flat maps and immunohistochemistry (human, monkey, rabbit, rat, mouse). The largest neurons in human cingulate cortex are in layer Vb of area 24 d in pMCC which project to the spinal cord. This area is part of the caudal cingulate premotor area which is involved in multisensory orientation of the head and body in space and neuron responses are tuned for the force and direction of movement. In contrast, the rostral cingulate premotor area in aMCC is involved in action-reinforcement associations and selection based on the amount of reward or aversive properties of a potential movement. The aMCC is activated by nociceptive information from the midline, mediodorsal and intralaminar thalamic nuclei which evoke fear and mediates nocifensive behaviors. This subregion also has high dopaminergic afferents and high dopamine-1 receptor binding and is engaged in reward processes. Opposing pain/avoidance and reward/approach functions are selected by assessment of potential outcomes and error detection according to feedback-mediated, decision making. Parietal afferents differentially terminate in MCC and provide for multisensory control in an eye- and head-centric manner. Finally, MCC vulnerability in human disease confirms the unique organization of MCC and supports the predictive validity of the MCC dichotomy. Vulnerability of aMCC is shown in chronic pain, obsessive-compulsive disorder with checking symptoms and attention-deficit/hyperactivity disorder and methylphenidate and pain medications selectively impact aMCC. In contrast, pMCC vulnerabilities are for progressive supranuclear palsy, unipolar depression and posttraumatic stress disorder. Thus, there is an emerging picture of the organization, functions and diseases of MCC. Future work will take this type of modular analysis to individual areas of which there are at least 10 in MCC.

Results of a prospective study (CATS) on the effects of thalamic stimulation in minimally conscious and vegetative state patients.

OBJECTIVE Deep brain stimulation of the thalamus was introduced more than 40 years ago with the objective of improving the performance and attention of patients in a vegetative or minimally conscious state. Here, the authors report the results of the Cortical Activation by Thalamic Stimulation (CATS) study, a prospective multiinstitutional study on the effects of bilateral chronic stimulation of the anterior intralaminar thalamic nuclei and adjacent paralaminar regions in patients affected by a disorder of consciousness. METHODS The authors evaluated the clinical and radiological data of 29 patients in a vegetative state (unresponsive wakefulness syndrome) and 11 in a minimally conscious state that lasted for more than 6 months. Of these patients, 5 were selected for bilateral stereotactic implantation of deep brain stimulating electrodes into their thalamus. A definitive consensus for surgery was obtained for 3 of the selected patients. All 3 patients (2 in a vegetative state and 1 in a minimally conscious state) underwent implantation of bilateral thalamic electrodes and submitted to chronic stimulation for a minimum of 18 months and a maximum of 48 months. RESULTS In each case, there was an increase in desynchronization and the power spectrum of electroencephalograms, and improvement in the Coma Recovery Scale-Revised scores was found. Furthermore, the severity of limb spasticity and the number and severity of pathological movements were reduced. However, none of these patients returned to a fully conscious state. CONCLUSIONS Despite the limited number of patients studied, the authors confirmed that bilateral thalamic stimulation can improve the clinical status of patients affected by a disorder of consciousness, even though this stimulation did not induce persistent, clinically evident conscious behavior in the patients. Clinical trial registration no.: NCT01027572 ( ClinicalTrials.gov ).

Impaired consciousness caused by injury of the lower ascending reticular activating system: evaluation by diffusion tensor tractography.

A 34-year-old male patient underwent conservative management for traumatic hemorrhage in the right frontal lobe (Figure 1A). The patient lost consciousness for approximately 4 weeks and experienced post-traumatic amnesia continuously from the time of the accident. The patient's Glasgow Coma Scale score (Teasdale et al., 1974) was 6 when he arrived at the hospital. At 5 weeks after onset, he was transferred to the rehabilitation department to undergo rehabilitation. Brain MRI showed malactic lesions in both the frontal lobes and right thalamus (Figure 1B). The patient exhibited impaired consciousness, with a Glasgow Coma Scale score of 9 and Coma Recovery Scale-Revised score of 8 (Giacino et al., 2004). Figure 1 Brain CT images, magnetic resonance images and diffusion tensor tractography (DTT) images of a 34-year-old male patient with traumatic brain injury. Diffusion tensor tractography (DTT) data were obtained at 6 weeks after onset using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Best, the Netherlands) with single-shot echo-planar imaging. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed matrix = 192 × 192; field of view = 240 × 240 mm2; repetition time = 10,726 ms; echo time = 76 ms; parallel imaging reduction factor (SENSE factor) = 2; EPI factor = 49; b = 1,000 s/mm2; number of excitations = 1; and a slice thickness of 2.5 mm. FACT algorithm was used for fiber tracking. For ascending reticular activating system (ARAS) analysis, the seed region of interest (ROI) was given on the pontine reticular formation. According to previous reports (Yeo et al., 2013; Jang et al., 2014), the target ROI was placed on the thalamic intralaminar nuclei to analyze the connectivity of the intralaminar nuclei. The patient showed intact neural connectivity between the thalamic intralaminar nuclei the frontal lobe. However, the left lower ARAS between pontine reticular formation and thalamic intralaminar nuclei was thinner than the right lower one of the same patient and those in five age-matched healthy control subjects (Figure 1C). In this study, we evaluated the ARAS in a patient with severe traumatic brain injury through two portions: First, three-dimensional reconstruction at the lower ARAS between the pontine reticular formation and the thalamic intralaminar nuclei, second, neural connectivity of the upper ARAS between the thalamic intralaminar nuclei and the cerebral cortex. Our results showed that the left lower ARAS was thinner than that of the right side of the patient and those of normal subjects. These findings appear to suggest an injury of the left lower ARAS. This injury was attributed to traumatic axonal injury because the conventional brain MRI of the patient was normal in the left thalamus and brainstem. Before analysis of the ARAS, we assumed that the main lesion would be located in the right ARAS and left upper ARAS because the brain MRI showed malactic lesions in both frontal lobes and the right thalamus. The main lesion site was detected in the left lower ARAS between the thalamic reticular formation and the thalamic intralaminar nuclei (Edlow et al., 2013; Jang et al., 2015a, b). Our results suggest that analysis of the ARAS using DTT would be useful for elucidating the cause of impaired consciousness. However, limitation of DTT with 1.5 T MRI should be considered, because a higher tesla MRI such as 3.0 T, can show better resolution and identify small tract more precisely. This work was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (MSIP), No. 2015R1A2A2A01004073.