The mesopontine tegmentum in reward and aversion: from cellular heterogeneity to behaviour.

The mesopontine tegmentum, comprising the pedunculopontine tegmentum (PPN) and the laterodorsal tegmentum (LDT), is intricately connected to various regions of the basal ganglia, motor systems, and limbic systems. The PPN and LDT can regulate the activity of different brain regions of these target systems, and in this way are in a privileged position to modulate motivated behaviours. Despite recent findings, the PPN and LDT have been largely overlooked in discussions about the neural circuits associated with reward and aversion. This review aims to provide a timely and comprehensive resource on past and current research, highlighting the PPN and LDT's connectivity and influence on basal ganglia and limbic, and motor systems. Seminal studies, including lesion, pharmacological, and optogenetic/chemogenetic approaches, demonstrate their critical roles in modulating reward/aversive behaviours. The review emphasizes the need for further investigation into the associated cellular mechanisms, in order to clarify their role in behaviour and contribution for different neuropsychiatric disorders.

Correlation between clinical and neuropathological subtypes of progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) is characterized by pathology prominently in the basal ganglia, the tegmentum of the brainstem, and the frontal cortex. However, pathology varies according to clinical features. This study aimed to statistically verify the correspondence between the clinical and pathological subtypes of PSP. METHODS: We identified patients with a pathological diagnosis of PSP and classified the eight clinical subtypes of the Movement Disorders Society criteria for the clinical diagnosis of PSP (MDS-PSP criteria) into the Richardson, Akinesia, and Cognitive groups. We used anti-phosphorylated tau antibody immunostaining to semi-quantitatively evaluate neurofibrillary tangles (NFTs) and coiled bodies/threads (CB/Ths) in the globus pallidus, subthalamic nucleus, and midbrain tegmentum. In the frontal cortex, tufted astrocytes (TAs) and CB/Ths were assessed on a 3-point scale. We compared the pathology among the three groups, recorded the phenotypes ranked the second and lower in the multiple allocation extinction rule and examined whether the pathology changed depending on applying each phenotype. RESULTS: The Richardson group exhibited severe NFTs and CB/Ths in the midbrain tegmentum. The Akinesia group showed severe NFTs in the globus pallidus. The Cognitive group had severe TAs and CB/Ths in the frontal cortex. TAs and CB/Ths in the frontal cortex correspond to behavioral variant frontotemporal dementia, and supranuclear vertical oculomotor palsy. CONCLUSION: These clinical symptoms may reflect the distribution of tau pathologies in PSP.

Inflammatory lesions of the brainstem: Keys for the diagnosis by MRI.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) findings for the most common inflammatory and immune-mediated diseases that involve the brainstem. CONCLUSION: Inflammatory lesions involving the brainstem are associated with a wide range of autoimmune, infectious, and paraneoplastic syndromes, making the differential diagnosis complex. Being familiar with these entities, their clinical characteristics, and their manifestations on MRI, especially the number of lesions, their shape and extension, and their appearance in different sequences, is useful for orienting the radiological diagnosis.

Lesiones inflamatorias del troncoencéfalo: claves diagnósticas en RM / Inflammatory lesions of the brainstem: Keys for the diagnosis by MRI

Objetivo: Describir los hallazgos en resonancia magnética (RM) de las principales enfermedades inflamatorias e inmunomediadas que afectan al troncoencéfalo. Conclusión: El diagnóstico diferencial de las lesiones inflamatorias localizadas en el troncoencéfalo es complicado debido al amplio espectro de enfermedades autoinmunes, infecciosas y síndromes paraneoplásicos que pueden causarlas. Conocer estas entidades, sus características clínicas y sus manifestaciones en RM, sobre todo en cuanto a número, morfología, extensión y apariencia en las diferentes secuencias, es útil a la hora de orientar el diagnóstico radiológico.(AU)

Objective: To describe the magnetic resonance imaging (MRI) findings for the most common inflammatory and immune-mediated diseases that involve the brainstem. Conclusion: Inflammatory lesions involving the brainstem are associated with a wide range of autoimmune, infectious, and paraneoplastic syndromes, making the differential diagnosis complex. Being familiar with these entities, their clinical characteristics, and their manifestations on MRI, particularly the number of lesions, their shape and extension, and their appearance in different sequences, is useful for orienting the radiological diagnosis.(AU)

Role of autonomic, nociceptive, and limbic brainstem nuclei in core autism features.

Although multiple theories have speculated about the brainstem reticular formation's involvement in autistic behaviors, the in vivo imaging of brainstem nuclei needed to test these theories has proven technologically challenging. Using methods to improve brainstem imaging in children, this study set out to elucidate the role of the autonomic, nociceptive, and limbic brainstem nuclei in the autism features of 145 children (74 autistic children, 6.0-10.9 years). Participants completed an assessment of core autism features and diffusion- and T1-weighted imaging optimized to improve brainstem images. After data reduction via principal component analysis, correlational analyses examined associations among autism features and the microstructural properties of brainstem clusters. Independent replication was performed in 43 adolescents (24 autistic, 13.0-17.9 years). We found specific nuclei, most robustly the parvicellular reticular formation-alpha (PCRtA) and to a lesser degree the lateral parabrachial nucleus (LPB) and ventral tegmental parabrachial pigmented complex (VTA-PBP), to be associated with autism features. The PCRtA and some of the LPB associations were independently found in the replication sample, but the VTA-PBP associations were not. Consistent with theoretical perspectives, the findings suggest that individual differences in pontine reticular formation nuclei contribute to the prominence of autistic features. Specifically, the PCRtA, a nucleus involved in mastication, digestion, and cardio-respiration in animal models, was associated with social communication in children, while the LPB, a pain-network nucleus, was associated with repetitive behaviors. These findings highlight the contributions of key autonomic brainstem nuclei to the expression of core autism features.

One node among many: sevoflurane-induced hypnosis and the challenge of an integrative network-level view of anaesthetic action.

Building on their known ability to influence sleep and arousal, Li and colleagues show that modulating the activity of glutamatergic pedunculopontine tegmental neurones also alters sevoflurane-induced hypnosis. This finding adds support for the shared sleep-anaesthesia circuit hypothesis. However, the expanding recognition of many neuronal clusters capable of modulating anaesthetic hypnosis raises the question of how disparate and anatomically distant sites ultimately interact to coordinate global changes in the state of the brain. Understanding how these individual sites work in concert to disrupt cognition and behaviour is the next challenge for anaesthetic mechanisms research.

Sex-dependent neuronal effects of α-synuclein reveal that GABAergic transmission is neuroprotective of sleep-controlling neurons.

BACKGROUND: Sleep disorders (SDs) are a symptom of the prodromal phase of neurodegenerative disorders that are mechanistically linked to the protein α-synuclein (α-syn) including Parkinson's disease (PD). SDs during the prodromal phase could result from neurodegeneration induced in state-controlling neurons by accumulation of α-syn predominant early in the disease, and consistent with this, we reported the monomeric form of α-syn (monomeric α-syn; α-synM) caused cell death in the laterodorsal tegmental nucleus (LDT), which controls arousal as well as the sleep and wakefulness state. However, we only examined the male LDT, and since sex is considered a risk factor for the development of α-syn-related diseases including prodromal SDs, the possibility exists of sex-based differences in α-synM effects. Accordingly, we examined the hypothesis that α-synM exerts differential effects on membrane excitability, intracellular calcium, and cell viability in the LDT of females compared to males. METHODS: Patch clamp electrophysiology, bulk load calcium imaging, and cell death histochemistry were used in LDT brain slices to monitor responses to α-synM and effects of GABA receptor acting agents. RESULTS: Consistent with our hypothesis, we found differing effects of α-synM on female LDT neurons when compared to male. In females, α-synM induced a decrease in membrane excitability and heightened reductions in intracellular calcium, which were reliant on functional inhibitory acid transmission, as well as decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) with a concurrent reduction in action potential firing rate. Cell viability studies showed higher α-synM-mediated neurodegeneration in males compared to females that depended on inhibitory amino acid transmission. Further, presence of GABA receptor agonists was associated with reduced cell death in males. CONCLUSIONS: When taken together, we conclude that α-synM induces a sex-dependent effect on LDT neurons involving a GABA receptor-mediated mechanism that is neuroprotective. Understanding the potential sex differences in neurodegenerative processes, especially those occurring early in the disease, could enable implementation of sex-based strategies to identify prodromal PD cases, and promote efforts to illuminate new directions for tailored treatment and management of PD.

From molecule to oblivion: dedicated brain circuitry underlies anesthetic loss of consciousness permitting pain-free surgery.

The canonical view of how general anesthetics induce loss-of-consciousness (LOC) permitting pain-free surgery posits that anesthetic molecules, distributed throughout the CNS, suppress neural activity globally to levels at which the cerebral cortex can no longer sustain conscious experience. We support an alternative view that LOC, in the context of GABAergic anesthesia at least, results from anesthetic exposure of a small number of neurons in a focal brainstem nucleus, the mesopontine tegmental anesthesia area (MPTA). The various sub-components of anesthesia, in turn, are effected in distant locations, driven by dedicated axonal pathways. This proposal is based on the observations that microinjection of infinitesimal amounts of GABAergic agents into the MPTA, and only there, rapidly induces LOC, and that lesioning the MPTA renders animals relatively insensitive to these agents delivered systemically. Recently, using chemogenetics, we identified a subpopulation of MPTA "effector-neurons" which, when excited (not inhibited), induce anesthesia. These neurons contribute to well-defined ascending and descending axonal pathways each of which accesses a target region associated with a key anesthetic endpoint: atonia, anti-nociception, amnesia and LOC (by electroencephalographic criteria). Interestingly, the effector-neurons do not themselves express GABAA-receptors. Rather, the target receptors reside on a separate sub-population of presumed inhibitory interneurons. These are thought to excite the effectors by disinhibition, thus triggering anesthetic LOC.

Wernekink Commissure Syndrome With Bilateral Cerebellar Signs and Holmes Tremor in a Patient With a Preexisting Movement Disorder.

Wernekink commissure syndrome (WCS) is an extremely rare midbrain syndrome, in which there is the selective destruction of the decussation of the superior cerebellar peduncle, which commonly presents with bilateral cerebellar signs. We describe a case of WCS with Holmes tremor in a patient having an undiagnosed involuntary movement disorder since childhood following an undocumented case of meningitis. The patient presented with sudden onset gait instability with bilateral cerebellar signs (more prominent on the left side), Holmes tremor in bilateral limbs, slurred speech, and marked dysarthria. No ophthalmoplegia or palatal tremors were noted. The patient was conservatively managed along the lines of a stroke, and there was a marked improvement in cerebellar signs and Holmes tremor with time but no evolution (improvement or worsening) was observed in the involuntary movements of limbs and face that were present before the onset of WCS.

Subtle magnetic resonance imaging differences in tegmental pilocytic astrocytomas as a caution against attempting gross-total resection: illustrative cases.

BACKGROUND: Although surgery within the tegmentum of the midbrain is challenging, resection of tegmental pilocytic astrocytomas (PAs) is a standard treatment because this has been shown to outperform chemotherapy and radiotherapy in terms of long-term tumor control. Gross total resection (GTR) assisted by intraoperative neuroelectrophysiological monitoring can be achieved with a reasonable risk-to-benefit ratio, especially for well-circumscribed tumors, but careful scrutiny of magnetic resonance imaging (MRI) is critical to surgical decision making. The authors present two cases of tegmental PAs, which appeared grossly similar on MRI and were operated on via the same surgical approach using the same intraoperative adjuncts. OBSERVATIONS: The tumors had identical histopathological and molecular diagnoses but drastically different functional outcomes for the patients, with significant long-term complications for one of the children, which the authors believe was due to a slightly more invasive nature of this tumor. The authors demonstrate subtle preoperative MRI findings that might be potential clues to a more infiltrative nature of one PA versus another and present pathological findings supporting this argument. LESSONS: This report serves as a reminder that not all tegmental PAs can be managed by the same surgical approach. Subtle signs of infiltration may indicate that GTR should not be attempted.

The laterodorsal tegmentum and seizure regulation: Revisiting the evidence.

Electrical deep brain stimulation (DBS) is now a routine treatment option for patients suffering from medically refractory epilepsy. DBS of the anterior nucleus of the thalamus (ANT) has proven to be effective but, despite its success, few patients experience complete cessation of seizure activity. However, improving the therapy is challenging because the mechanism underlying its action remains largely unknown. One angle on improving the effectiveness of ANT stimulation is to better understand the various anatomic regions that send projections to and through this area. Here, the authors utilized a connectomic atlas of the mouse brain to better understand the regions projecting to the ANT and were particularly interested by the presence of robust cholinergic projections from the laterodorsal tegmentum (LDT). A subsequent review of the literature resulted in limited studies, which presented convincing evidence supporting this region's role in seizure control present in acute rodent models of epilepsy. It is thus the purpose of this paper to encourage further research into the role of the LDT on seizure mitigation, with mechanistic effects likely stemming from its cholinergic projections to the ANT. While previous studies have laid a firm foundation supporting the role of this region in modulation of seizure activity, modern scientific methodology has yet to be applied to further elucidate the mechanisms and potential benefits associated with LDT stimulation in the epileptic population.

Transcription Factors as Important Regulators of Changes in Behavior through Domestication of Gray Rats: Quantitative Data from RNA Sequencing.

Studies on hereditary fixation of the tame-behavior phenotype during animal domestication remain relevant and important because they are of both basic research and applied significance. In model animals, gray rats Rattus norvegicus bred for either an enhancement or reduction in defensive response to humans, for the first time, we used high-throughput RNA sequencing to investigate differential expression of genes in tissue samples from the tegmental region of the midbrain in 2-month-old rats showing either tame or aggressive behavior. A total of 42 differentially expressed genes (DEGs; adjusted p-value < 0.01 and fold-change > 2) were identified, with 20 upregulated and 22 downregulated genes in the tissue samples from tame rats compared with aggressive rats. Among them, three genes encoding transcription factors (TFs) were detected: Ascl3 was upregulated, whereas Fos and Fosb were downregulated in tissue samples from the brains of tame rats brain. Other DEGs were annotated as associated with extracellular matrix components, transporter proteins, the neurotransmitter system, signaling molecules, and immune system proteins. We believe that these DEGs encode proteins that constitute a multifactorial system determining the behavior for which the rats have been artificially selected. We demonstrated that several structural subtypes of E-box motifs­known as binding sites for many developmental TFs of the bHLH class, including the ASCL subfamily of TFs­are enriched in the set of promoters of the DEGs downregulated in the tissue samples of tame rats'. Because ASCL3 may act as a repressor on target genes of other developmental TFs of the bHLH class, we hypothesize that the expression of TF gene Ascl3 in tame rats indicates longer neurogenesis (as compared to aggressive rats), which is a sign of neoteny and domestication. Thus, our domestication model shows a new function of TF ASCL3: it may play the most important role in behavioral changes in animals.

The parabigeminal nucleus is a source of "retinogeniculate replacement terminals" in mice that lack retinofugal input.

In the dorsal lateral geniculate nucleus (LGN) of mice that lack retinal input, a population of large terminals supplants the synaptic arrangements normally made by the missing retinogeniculate terminals. To identify potential sources of these "retinogeniculate replacement terminals," we used mutant mice (math5-/- ) which lack retinofugal projections due to the failure of retinal ganglion cells to develop. In this line, we labeled LGN terminals that originate from the primary visual cortex (V1) or the parabigeminal nucleus (PBG), and compared their ultrastructure to retinogeniculate, V1 or PBG terminals in the dLGN of C57Blk6 (WT) mice (schematically depicted above graph). Corticogeniculate terminals labeled in WT and math5-/- mice were similar in size and both groups were significantly smaller than WT retinogeniculate terminals. In contrast, the PBG projection in math5-/- mice was extensive and there was considerable overlap in the sizes of retinogeniculate terminals in WT mice and PBG terminals in math5-/- mice (summarized in histogram). The data indicate that V1 is not a source of "retinogeniculate replacement terminals" and suggests that large PBG terminals expand their innervation territory to replace retinogeniculate terminals in their absence.

An inhibitory brainstem input to dopamine neurons encodes nicotine aversion.

Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotine involve desensitization of α4ß2 and activation of α7 nicotinic acetylcholine receptors. We identify α7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA prevents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.

Anesthetic loss of consciousness induced by chemogenetic excitation of mesopontine effector neurons.

Although general anesthesia is normally induced by systemic dosing, an anesthetic state can be induced in rodents by microinjecting minute quantities of GABAergic agents into the brainstem mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesions to the MPTA render rats relatively insensitive to standard anesthetic doses delivered systemically. Using a chemogenetic approach we have identified and characterized a small subpopulation of neurons restricted to the MPTA which, when excited, render the animal anesthetic by sensorimotor (immobility) and electroencephalographic (EEG) criteria. These "effector-neurons" do not express GABAAδ-Rs, the likely target of GABAergic anesthetics. Rather, we report a distinct sub-population of nearby MPTA neurons which do. During anesthetic induction these likely excite the effector-neurons by disinhibition. Within the effector population ~ 70% appear to be glutamatergic, ~30% GABAergic and ~ 40% glycinergic. Most are projection neurons that send ascending or descending axons to distant targets associated with the individual functional components of general anesthesia: atonia, analgesia, amnesia, and loss-of-consciousness.

Molecular analyses of rosette-forming glioneuronal tumor of the midbrain tegmentum: A report of two cases and a review of the FGFR1 status in unusual tumor locations.

Background: Rosette-forming glioneuronal tumor (RGNT) is a rare tumor that arises primarily in the posterior fossa, with molecular features of FGFR1 mutation. A previous study reported that brainstem RGNT accounts for only 2.7% cases; therefore, midbrain RGNT is infrequent. Case Description: The authors encountered two cases of RGNT located in the midbrain tegmentum (Case 1: 23-year-old woman and Case 2: 18-year-old boy), both exhibiting similar cystic components with gadolinium-enhanced cyst walls on preoperative magnetic resonance imaging, surgically resected through the occipital transtentorial approach. Histological findings in both cases comprised two characteristic architectures of neurocytic and glial components, typical of RGNT. Molecular assessment revealed no FGFR1 mutation in the initial specimen, but revealed FGFR1 K656E mutation in the recurrent specimen in Case 1 and showed no FGFR1 mutation but showed TERT C228T mutation in Case 2. Neither case revealed IDH1/2, BRAF, H3F3A K27, H3F3A G34, or HIST1H3B K27 mutations. DNA methylation-based classification (molecularneuropathology.org) categorized both cases as RGNT, whose calibrated scores were 0.99 and 0.47 in Cases 1 and 2, respectively. Conclusion: Midbrain tegmentum RGNTs exhibited typical histological features but varied FGFR1 statuses with TERT mutation. RGNT in rare locations may carry different molecular alterations than those in other common locations, such as the posterior fossa.

Resolving dyskinesias at sustained anti-OCD efficacy by steering of DBS away from the anteromedial STN to the mesencephalic ventral tegmentum - case report.

Here we describe therapeutic results in a female patient who underwent bilateral slMFB DBS for OCD. During a 35-month long course of stimulation, she suffered from stimulation-induced dyskinesia of her right leg which we interpreted as co-stimulation of the adjacent anteromedial subthalamic nucleus (amSTN). After reprogramming to steer the stimulation away from the amSTN medial into the direction of the mesencephalic ventral tegmentum (MVT which contains the ventral tegmental area, VTA), the dyskinesias disappeared. Remarkably, anti-OCD efficacy in the presented patient was preserved and achieved with a bilateral stimulation which by our imaging study fully avoided the amSTN.

Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence.

As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.

Might pain be experienced in the brainstem rather than in the cerebral cortex?

It is nearly axiomatic that pain, among other examples of conscious experience, is an outcome of still-uncertain forms of neural processing that occur in the cerebral cortex, and specifically within thalamo-cortical networks. This belief rests largely on the dramatic relative expansion of the cortex in the course of primate evolution, in humans in particular, and on the fact that direct activation of sensory representations in the cortex evokes a corresponding conscious percept. Here we assemble evidence, drawn from a number of sources, suggesting that pain experience is unlike the other senses and may not, in fact, be an expression of cortical processing. These include the virtual inability to evoke pain by cortical stimulation, the rarity of painful auras in epileptic patients and outcomes of cortical lesions. And yet, pain perception is clearly a function of a conscious brain. Indeed, it is perhaps the most archetypical example of conscious experience. This draws us to conclude that conscious experience, at least as realized in the pain system, is seated subcortically, perhaps even in the "primitive" brainstem. Our conjecture is that the massive expansion of the cortex over the course of evolution was not driven by the adaptive value of implementing consciousness. Rather, the cortex evolved because of the adaptive value of providing an already existing subcortical generator of consciousness with a feed of critical information that requires the computationally intensive capability of the cerebral cortex.

Right Tegmental Hemorrhage with Urinary Retention: A Case Report.

The upper brainstem tegmentum is dense and complex, making it difficult to localize functions to specific subregions. In particular, the precise location and possible laterality of subregions supporting basic functions like consciousness and urinary continence remain unclear. Here, we describe a patient who presented with a right pontine tegmental syndrome caused by intraparenchymal hemorrhage. Despite hemorrhage extension into the fourth ventricle and expansion of both hemorrhage and edema into a large region of the caudal midbrain and right-sided pontine tegmentum, this patient did not lose consciousness. Instead, he developed new and total urinary retention, with residual bladder volumes of more than 1,000 mL. We conclude that injury to the right pontine tegmentum is sufficient to disrupt the micturition reflex pathway.