ExPPNing how acetylcholine improves gait in Parkinson's disease: An Editorial Highlight for 'Deletion of the Vesicular Acetylcholine Transporter from Pedunculopontine/laterodorsal tegmental neurons modifies gait'.

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Physiology of midbrain head movement neurons in cervical dystonia.

BACKGROUND: Early theories for cervical dystonia, as promoted by Hassler, emphasized the role of the midbrain interstitial nucleus of Cajal. Focus then shifted to the basal ganglia, and it was further supported with the success of deep brain stimulation. Contemporary theories suggested the role of the cerebellum, but even more recent hypotheses renewed interest in the midbrain. Although the pretectum was visited on several occasions, we still do not know about the physiology of midbrain neurons in cervical dystonia. METHODS: We analyzed the unique database of pretectal neurons collected in the 1970s and 1980s during historic stereotactic surgeries aimed to treat cervical dystonia. This database is valuable because such recordings could otherwise never be obtained from humans. RESULTS: We found the following 3 types of eye or neck movement sensitivity: eye-only neurons responded to pure vertical eye movements, neck-only neurons were sensitive to pure neck movements, and the combined eye-neck neurons responded to eye and neck movements. There were the 2 neuronal subtypes: burst-tonic and tonic. The eye-neck or eye-only neurons sustained their activity during eccentric gaze holding. In contrast, the response of neck-only and eye-neck neurons exponentially decayed during neck movements. CONCLUSIONS: Modern quantitative analysis of a historic database of midbrain single units from patients with cervical dystonia might support novel hypotheses for normal and abnormal head movements. This data, collected almost 4 decades ago, must be carefully viewed, especially because it was acquired using a less sophisticated technology available at that time and the aim was not to address specific hypothesis, but to make an accurate lesion providing optimal relief from dystonia. © 2017 International Parkinson and Movement Disorder Society.

The role of neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus for cocaine addiction.

A large body of literature indicates that neural adaptations induced by cocaine in the mesocorticolibic system cause addictive behaviors. Emerging evidence suggests that the laterdorsal tegmental nucleus (LDT), which contains cholinergic, glutamatergic and GABAergic neurons and innervates the ventral tegmental area (VTA), might also contribute to the development of cocaine addiction. In this review, we summarize our recent findings showing that neuroplasticity elicited by cocaine administration in LDT cholinergic neurons is involved in the expression of addictive behaviors. Ex vivo electrophysiological recordings obtained from repeatedly cocaine administered rats revealed and increased excitatory synaptic transmission to and enhanced intrinsic membrane excitability in LDT cholinergic neurons. The former depended on enhanced glutamate release probability form presynaptic terminals and the latter was mediated by increased persistent sodium conductance. Additionally, intra-LDT administration of AMPA/HMDA receptor antagonists or a persistent sodium channel blocker attenuated the expression of cocaine-induced conditioned place preference. These findings suggest that chronic cocaine exposure-induced neuroplasticity in LDT cholinergic neurons may activate LDT cholinergic neurons, which in turn may enhance the activity of dopamine neurons in the VTA, leading to the development of cocaine addiction.

Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior.

The laterodorsal tegmental nucleus (LDT) is a brainstem nucleus implicated in reward processing and is one of the main sources of cholinergic afferents to the ventral tegmental area (VTA). Neuroplasticity in this structure may affect the excitability of VTA dopamine neurons and mesocorticolimbic circuitry. Here, we provide evidence that cocaine-induced intrinsic membrane plasticity in LDT cholinergic neurons is involved in addictive behaviors. After repeated experimenter-delivered cocaine exposure, ex vivo whole-cell recordings obtained from LDT cholinergic neurons revealed an induction of intrinsic membrane plasticity in regular- but not burst-type neurons, resulting in increased firing activity. Pharmacological examinations showed that increased riluzole-sensitive persistent sodium currents, but not changes in Ca(2+) -activated BK, SK or voltage-dependent A-type potassium conductance, mediated this plasticity. In addition, bilateral microinjection of riluzole into the LDT immediately before the test session in a cocaine-induced conditioned place preference (CPP) paradigm inhibited the expression of cocaine-induced CPP. These findings suggest that intrinsic membrane plasticity in LDT cholinergic neurons is causally involved in the development of cocaine-induced addictive behaviors.

Allodynia and descending pain modulation in migraine: a resting state functional connectivity analysis.

OBJECTIVE: Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions. DESIGN: Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls. RESULTS: Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls. CONCLUSION: Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.

Psychiatric disorder-related abnormal behavior and habenulointerpeduncular pathway defects in Wnt1-cre and Wnt1-GAL4 double transgenic mice.

The neural crest is a unique structure in vertebrates. Wnt1-cre and Wnt1-GAL4 double transgenic (dTg) mice have been used in a variety of studies concerning neural crest cell lineages in which the Cre/loxP or GAL4/UAS system was applied. Here, we show psychiatric disorder-related behavioral abnormalities and histologic alterations in a neural crest-derived brain region in dTg mice. The dTg mice exhibited increased locomotor activity, decreased social interaction, and impaired short-term spatial memory and nesting behavior. The choline acetyltransferase- and vesicular glutamate transporter 2-immunoreactive habenulointerpeduncular fiber tracts that project from the medial habenular nucleus of the epithalamus to the interpeduncular nucleus of the midbrain tegmentum appeared irregular in the dTg mice. Both the medial habenula nucleus and the interpeduncular nucleus were confirmed to be derived from the neural crest. The findings of this study suggest that neural crest-derived cells have pathogenic roles in the development of psychiatric disorders and that the dTg mouse could be a useful animal model for studying the pathophysiology of mental illness such as autism and schizophrenia. Scientists that use the dTg mice as a cre-transgenic deleter line should be cautious in its possible toxicity, especially if behavioral analyses are to be performed.

Human periventricular grey somatosensory evoked potentials suggest rostrocaudally inverted somatotopy.

BACKGROUND: Somatosensory homunculi have been demonstrated in primary somatosensory cortex and ventral posterior thalamus but not periaqueductal and periventricular grey matter (PAVG), a therapeutic target for deep brain stimulation (DBS) in chronic pain. AIMS: The study is an investigation of somatotopic representation in PAVG and assessment for a somatosensory homunculus. METHODS: Five human subjects were investigated using electrical somatosensory stimulation and deep brain macroelectrode recording. DBS were implanted in the contralateral PAVG. Cutaneous arm, leg and face regions were stimulated while event-related potentials were recorded from deep brain electrodes. Electrode contact positions were mapped using MRI and brain atlas information. RESULTS: Monopolar P1 somatosensory evoked potential amplitudes were highest and onset latencies shortest in contralateral caudal PAVG with facial stimulation and rostral with leg stimulation, in agreement with reported subjective sensation during intra-operative electrode advancement. CONCLUSIONS: A rostrocaudally inverted somatosensory homunculus exists in the human PAVG region. Objective human evidence of PAVG somatotopy increases understanding of a brainstem region important to pain and autonomic control that is a clinical target for both pharmacological and neurosurgical therapies. Such knowledge may assist DBS target localisation for neuropathic pain syndromes related to particular body regions like brachial plexopathies, anaesthesia dolorosa and phantom limb pain.

Diffusion tensor imaging for intracerebral hemorrhage outcome prediction: comparison using data from the corona radiata/internal capsule and the cerebral peduncle.

BACKGROUND: Magnetic resonance-diffusion tensor imaging (DTI) was used to predict motor outcome for patients with intracerebral hemorrhage. We compared the predictive accuracy of data sampled from the cerebral peduncle with data from the corona radiata/internal capsule. This study included 32 subjects with thalamic or putaminal hemorrhage or both. METHODS: DTI data were obtained on days 14 to 18. Mean values of fractional anisotropy (FA) within the cerebral peduncle and the corona radiata/internal capsule were analyzed using a computer-automated method. Applying ordinal logistic regression analyses, the ratios between FA values in the affected and unaffected hemisphere (rFA) were modeled in relation to motor outcome scores at 1 month after onset, assessed using the Medical Research Council (MRC) scale (0 = null to 5 = full). RESULTS: For both cerebral peduncle and corona radiata/internal capsule, the relationships between rFA and MRC matched logistic probabilities. While cerebral peduncle rFA values had statistically significant relationships with MRC scores (upper extremity R(2) = 0.271; lower extremity R(2) = 0.191), rFA values for the corona radiata/internal capsule showed less significant relationships (upper extremity R(2) = 0.085; lower extremity R(2) = 0.080). When estimated cerebral peduncle rFA values were <0.7, estimated probability of MRC 0 to 2 was close to 85% for the upper and 60% for the lower extremities. Meanwhile, when estimated rFA values were >0.9, estimated probability for MRC 4 to 5 nearly equaled 50% for the upper and 60% for the lower extremities. CONCLUSIONS: FA values from within the cerebral peduncle more accurately predicted motor outcome and is a promising technique for clinical application.

Prediction of motor function outcome after intracerebral hemorrhage using fractional anisotropy calculated from diffusion tensor imaging.

BACKGROUND: The efficacy of surgical evacuation in patients with intracerebral hemorrhage (ICH) remains unclear for recovery of motor function. The relationship between improvement of motor function outcome and sequential change of fractional anisotropy (FA) values was investigated in patients with ICH, to explore whether motor function outcome can be predicted in the early phase. Indication of the surgical hematoma evacuation was also considered. METHODS: This prospective study included 23 patients with ICH. All patients underwent diffusion tensor imaging to measure the FA value five times: within 3 days, day 14, day 30, day 60, and day 90 after the onset. The regions of interest were determined on the b = 0 step of the echo planar imaging scans in the bilateral cerebral peduncles and were automatically transferred onto the FA images. The FA value was then calculated for each patient. Patients were divided into good and poor recovery groups according to the motor function outcome on day 90. RESULTS: The mean FA value of the poor recovery group gradually decreased until day 90, but remained unchanged in the good recovery group. The mean FA value on day 3 was significantly higher (p < 0.001) in the good recovery group (0.745 ± 0.0073) than in the poor recovery group (0.682 ± 0.0090). Receiver operating characteristic curve analysis showed that the FA value on day 3 could predict motor function outcome with a sensitivity of 100% and a specificity of 77.8% at an FA value of 0.7 on day 3. CONCLUSION: The main finding of this study was that the FA values of the cerebral peduncle on the pathological side in patients with ICH on day 3 could predict the motor function outcome on day 90.

Deep brain stimulation in cluster headache: hypothalamus or midbrain tegmentum?

Functional and structural neuroimaging studies have provided pivotal insights into the pathophysiology of trigeminal autonomic cephalalgias (TACs), particularly cluster headache (CH). Functional imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in TACs have reported activation of the posterior hypothalamus. A structural neuroimaging study using voxel-based morphometry in CH reported increased volume of the hypothalamic gray, although another larger study failed to reproduce this finding. These studies in CH prompted the use of stereotactic stimulation of the target point identified by functional and structural neuroimaging. The precise anatomical localization of the deep brain stimulation (DBS) target places it at the midbrain tegmentum rather than the posterior hypothalamus. A comparison of the PET and fMRI studies in TACs reveals that the diencephalic/mesencephalic activation is more posteroinferior in the PET studies, straddling the hypothalamus and midbrain tegmentum, whereas the activation is centered on the hypothalamus in the higher spatial resolution fMRI studies. To optimize the outcomes from DBS, it is likely that patients will need to be studied individually using functional imaging techniques that have high spatial and temporal resolution to enable targeting of the appropriate locus with stereotactic stimulation.

The limbic circuitry underlying cocaine seeking encompasses the PPTg/LDT.

The direct glutamatergic projection from the medial prefrontal cortex (mPFC) to the nucleus accumbens plays a critical role in mediating the reinstatement of cocaine seeking behavior. The mPFC also sends glutamatergic projections to the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDT), which in turn send glutamatergic and cholinergic efferents to the ventral tegmental area (VTA) where they synapse on dopaminergic cells that innervate limbic structures including the nucleus accumbens. The goal of these experiments was to examine a potential role for the PPTg/LDT in the reinstatement of cocaine seeking. All rats were trained to self-administer cocaine (0.25 mg, i.v.) on a fixed-ratio 5 schedule of reinforcement. Cocaine self-administration behavior was extinguished and a series of subsequent pharmacological experiments were performed to assess the potential role of the mPFC, PPTg/LDT and VTA in the reinstatement of cocaine seeking. Administration of the D1-like dopamine receptor agonist SKF-81297 (1.0 microg) directly into the mPFC produced a small, but statistically significant, increase in cocaine seeking behavior. Furthermore, microinjection of the ionotropic glutamate receptor antagonist CNQX (0.3 microg) into the PPTg/LDT attenuated the reinstatement of drug seeking induced by a priming injection of cocaine (10 mg/kg, i.p.). Intra-VTA administration of CNQX, the nicotinic receptor antagonist mecamylamine (10.0 microg) or the muscarinic receptor antagonist scopolamine (24.0 microg) also blocked cocaine seeking. Taken together, these results suggest that cocaine priming-induced reinstatement of drug seeking is mediated in part by a serial polysynaptic limbic subcircuit encompassing the mPFC, PPTg/LDT and VTA.

Abnormal Eye Position Signals in Interstitial Nucleus of Cajal in Monkeys With "A" Pattern Strabismus.

Purpose: Pattern strabismus is characterized by a cross-axis pattern of horizontal and vertical misalignments. In A-pattern strabismus, for example, a divergent change in the horizontal misalignment occurs on downgaze. Work with nonhuman primate models has provided evidence that this disorder is associated with abnormal cross-talk between brainstem pathways that normally encode horizontal and vertical eye position and velocity. Neurons in the interstitial nucleus of Cajal (INC) are normally sensitive to vertical eye position; in the present study, we test the hypothesis that, in monkeys with pattern strabismus, some INC neurons will show an abnormal sensitivity to horizontal eye position. Methods: Monkeys were rewarded for fixating a visual target that stepped to various locations on a tangent screen. Single neurons were recorded from INC in one normal monkey, and two with A-pattern strabismus. Multiple linear regression analysis was used to estimate the preferred direction for each neuron. Results: In the normal monkey, all INC neurons had preferred directions within 20° of pure vertical (either up or down). The preferred directions were significantly more variable in the monkeys with pattern strabismus, with a minority being more sensitive to horizontal eye position than vertical eye position. In addition, the vertical eye position sensitivity was significantly less in the monkeys with strabismus. Conclusions: In pattern strabismus, neurons in INC show neurophysiological abnormalities consistent with a failure to develop normal tuning properties. Results were consistent with the hypothesis that, in pattern strabismus, INC receives an abnormally strong signal related to horizontal eye position.

Combining quantitative susceptibility mapping to the morphometric index in differentiating between progressive supranuclear palsy and Parkinson's disease.

PURPOSE: To determine whether the susceptibility value in the deep gray matter obtained by quantitative susceptibility mapping (QSM) provides additive value to the morphometric index for differentiating progressive supranuclear palsy (PSP) from Parkinson's disease (PD). MATERIALS AND METHODS: PSP- (n = 8) and PD patients (n = 18) and 18 age-matched healthy controls who underwent QSM and 3D magnetization-prepared rapid gradient echo (MPRAGE) sequences. The mean susceptibility values (MSVs) of the deep gray matter structures on QSM- and areas of the midbrain (morphometric index, MI) on 3D MPRAGE images were measured by two neuroradiologists. Analysis of variance, the Scheffe test and receiver operating characteristic (ROC) analysis were conducted to assess differences and discriminate among PSP, PD and controls by the MSVs and the MI. Using the MSV of a structure with the best area under the curve (AUC) and the MI, we created a decision tree to differentiate between PSP and PD. RESULTS: The MSVs of the globus pallidus (GP) and substantia nigra (SN) were significantly higher in PSP than PD and the controls (p < .05). By ROC analysis (PSP vs PD), AUC was greatest (0.903) for the GP. The MI was significantly smaller in PSP than PD and the controls (p < .05); AUC (PSP vs PD) was 0.917. The decision tree using cutoff values of 244 parts per billion for MSV of the GP and 74.0 mm2 for MI served to completely differentiate between PSP and PD. CONCLUSION: The MSV in the GP on QSM images adds value to the MI for differentiating PSP from PD.

Wall-eyed bilateral internuclear ophthalmoplegia in a patient with progressive supranuclear palsy.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a rare disorder consisting of a bilateral adduction deficit and primary gaze position exotropia. Associated with bilateral medial longitudinal fasciculus lesions, it has been mostly reported in patients with multiple sclerosis and brainstem stroke. A 72-year-old man with characteristic clinical features of progressive supranuclear palsy (PSP) later developed WEBINO. Brain MRI revealed atrophy of the midbrain tegmentum. Caloric irrigation revealed intact horizontal eye movements in both eyes. We believe this to be the first report of WEBINO in PSP. The preservation of vestibulo-ocular horizontal eye movements supports the notion that the WEBINO in this condition was caused by a supranuclear rather than a nuclear lesion and suggests the possibility that even in other causes of WEBINO, the lesion is supranuclear and not in the medial rectus subnucleus as is often suggested.

Dissociated palsy of vertical saccades: loss of voluntary and visually guided saccades with preservation of reflexive vestibular quick phases.

A patient with a diencephalic infarct displayed a persistent palsy of voluntary and visually guided vertical saccades with preserved vertical quick phases of vestibular nystagmus on magnetic search coil oculography. Vertical smooth pursuit had very low velocity in both directions without catch-up saccades. Vertical and torsional vestibulo-ocular reflex gains were normal. Preservation of vertical and torsional quick phases signifies integrity of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). This case is the first to provide evidence that disruption of descending cerebral corticofugal pathways to the riMLF with preserved ascending projections from the paramedian pontine reticular formation to the riMLF can cause a dissociated palsy of vertical fast eye movements.

Bimedial rectus hypermetabolism in convergence spasm as observed on positron emission tomography.

A 52-year-old man developed vertical gaze palsy, convergence spasm, and convergence-retraction nystagmus due to glioblastoma of the right thalamus. 18F-fluorodeoxyglucose positron emission tomography (PET) inadvertently demonstrated markedly increased metabolism in the medial rectus muscles. The hypermetabolism indicates active contraction of these extraocular muscles due to excessive convergence drive attributed to inappropriate activation or disrupted inhibition of convergence neurons by the diencephalic lesion.

Magnetic resonance correlate of hemiparesis in posterior cerebral artery infarction.

BACKGROUND: Magnetic resonance (MR) imaging of posterior cerebral artery infarction with hemiparesis (PCAH) is limited to case reports with T2-weighted lesions involving the cerebral peduncle. OBJECTIVE: We sought to extend the MR imaging correlate of PCAH. METHODS: The case histories and MR/MR angiography findings of 4 patients with PCAH were examined. RESULTS: Distinct from previously described MR imaging findings with PCAH, diffusion-weighted imaging and/or FLAIR changes were noted in the thalamogeniculate artery (TGA) territory in one patient; in the distribution of the TGA and lateral posterior choroidal artery (PChA) in two patients; and in the TGA and lateral PChA combined with the peduncular perforating arteries of the cerebral peduncle in one patient. CONCLUSION: Diffusion-weighted imaging changes of infarction in the distribution of the TGA alone or combined with lateral PChA involvement with or without cerebral peduncle infarction correlate with PCAH.

Enhanced wakefulness following lesions of a mesopontine locus essential for the induction of general anesthesia.

The induction of general anesthesia shares many features with the transition from wakefulness to non-rapid eye movement (NREM) sleep, suggesting that the two types of brain-state transition are orchestrated by a common neuronal mechanism. Previous studies revealed a brainstem locus, the mesopontine tegmental anesthesia area (MPTA), that is of singular importance for anesthetic induction. Microinjection of GABAergic anesthetics there induces rapid loss-of-consciousness and lesions render the animal relatively insensitive to anesthetics administered systemically. Here we show that MPTA lesions also alter the natural sleep-wake rhythm by increasing overall wake time at the expense of time asleep (NREM and REM sleep equally), with nearly all of the change occurring during the dark hours of the light-dark cycle. The effect was proportional to the extent of the lesion and was not seen after lesions just outside of the MPTA, or following sham lesions. Thus, MPTA neurons appear to play a role in natural bistable brain-state switching (sleep-wake) as well as in loss and recovery of consciousness induced pharmacologically.

Frontal-lobe syndrome and psychosis after damage to the brainstem dopaminergic nuclei.

A patient developed frontal-lobe syndrome and psychotic symptoms after infarction in the pontomesencephalic junction. Stereotaxic lesion localization on magnetic resonance imaging and statistical analyses of regional cerebral blood flow (rCBF) disclosed an involvement of the rostral brainstem dopaminergic nuclei and hypoperfusion in the frontal-subcortical circuit components. We suggest that the patient's cognitive and behavioral disturbances were associated with disruption of ascending dopaminergic projections to the frontal-subcortical circuits.

Peduncular hallucinosis after sacrifice of veins of the petrosal venous complex for trigeminal neuralgia.

Peduncular hallucinosis is characterized by striking visual images, highly colored and mobile, which are recognized by the patient as imaginary. A 50-year-old-man underwent microvascular decompression for a classical right sided trigeminal neuralgia. During the procedure, the petrosal vein and a transverse pontine vein were sacrificed for trigeminal decompression. On the second postoperative day, the patient developed peduncular hallucinosis that disappeared on the forth postoperative day. This is the third case in the literature of peduncular hallucinosis after obliteration of veins of the petrosal venous complex for trigeminal neuralgia. The best policy in cerebellopontine angle surgery is to preserve the petrosal vein whenever possible to avoid complications related to venous congestion.