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.

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.

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.

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.

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'.

Read the highlighted article 'Deletion of the Vesicular Acetylcholine Transporter from Pedunculopontine/laterodorsal tegmental neurons modifies gait' on page 787.

Effects of early-life exposure to THIP on brainstem neuronal excitability in the Mecp2-null mouse model of Rett syndrome before and after drug withdrawal.

Rett syndrome (RTT) is mostly caused by mutations of the X-linked MECP2 gene. Although the causal neuronal mechanisms are still unclear, accumulating experimental evidence obtained from Mecp2-/Y mice suggests that imbalanced excitation/inhibition in central neurons plays a major role. Several approaches may help to rebalance the excitation/inhibition, including agonists of GABAA receptors (GABAAR). Indeed, our previous studies have shown that early-life exposure of Mecp2-null mice to the extrasynaptic GABAAR agonist THIP alleviates several RTT-like symptoms including breathing disorders, motor dysfunction, social behaviors, and lifespan. However, how the chronic THIP affects the Mecp2-/Y mice at the cellular level remains elusive. Here, we show that the THIP exposure in early lives markedly alleviated hyperexcitability of two types of brainstem neurons in Mecp2-/Y mice. In neurons of the locus coeruleus (LC), known to be involved in breathing regulation, the hyperexcitability showed clear age-dependence, which was associated with age-dependent deterioration of the RTT-like breathing irregularities. Both the neuronal hyperexcitability and the breathing disorders were relieved with early THIP treatment. In neurons of the mesencephalic trigeminal nucleus (Me5), both the neuronal hyperexcitability and the changes in intrinsic membrane properties were alleviated with the THIP treatment in Mecp2-null mice. The effects of THIP on both LC and Me5 neuronal excitability remained 1 week after withdrawal. Persistent alleviation of breathing abnormalities in Mecp2-/Y mice was also observed a week after THIP withdrawal. These results suggest that early-life exposure to THIP, a potential therapeutic medicine, appears capable of controlling neuronal hyperexcitability in Mecp2-/Y mice, which occurs in the absence of THIP in the recording solution, lasts at least 1 week after withdrawal, and may contribute to the RTT-like symptom mitigation.

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.

Lesions of the laterodorsal tegmental nucleus alter the cholinergic innervation and neuropeptide Y expression in the medial prefrontal cortex and nucleus accumbens.

The effects of the ibotenic acid infused into the area of the laterodorsal tegmental nucleus (LDT) of rats on the expression of cortical and accumbal neuropeptides were assessed. The effects of this manipulation were determined in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) by estimating the numerical density of varicosities immunoreactive for vesicular acetylcholine transporter and the total number of NAc neurons immunoreactive for choline acetyltransferase (ChAT) and neuropeptide Y (NPY) as well as the total number of mPFC neurons immunoreactive for NPY and vasoactive intestinal polypeptide (VIP). In LDT-lesioned rats, the density of the cholinergic varicosities was reduced in the ventral divisions of the mPFC and in all divisions of the NAc. In addition, in these rats, the total number of NPY-immunoreactive neurons was reduced in all subregions of the mPFC and in the NAc. Conversely, the total number of VIP-immunoreactive neurons in the mPFC and of ChAT-immunoreactive neurons in the NAc did not differ between LDT- and sham-lesioned rats. These data provide the first direct evidence for a relationship between selective damage of LDT cholinergic neurons and decreased expression of NPY in the mPFC and NAc. They also reveal that different types of cortical and accumbal interneurons respond differently to the cholinergic denervation induced by LDT lesions.

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.

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.

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.

Dopaminergic involvement during mental fatigue in health and cocaine addiction.

Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on-task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction.

Evolution of abnormal eye movements in Wernicke's encephalopathy: correlation with serial MRI findings.

A 33-year-old woman with Wernicke's encephalopathy (WE) due to poor oral intake after allogeneic stem cell transplantation for acute myeloid leukemia showed a sequential development of bilateral gaze-evoked nystagmus (GEN), rightward gaze palsy, and upbeat nystagmus. Initial MRIs obtained when she had GEN only showed a lesion involving the medullary tegmentum, and follow-up MRIs revealed additional lesions in the pontine and midbrain tegmentum along with development of rightward gaze palsy, and finally bilateral medial thalamus lesions in association with upbeat nystagmus. The evolution of abnormal ocular motor findings and serial MRI changes in our patient with WE provide imaging evidence on relative vulnerability of the neural structures, and on the progression of lesions and ocular motor findings in thiamine deficiency.

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.

La sustancia blanca en los trastornos del desarrollo / White matter in developmental disorders

La sustancia blanca supone el principal conector entre distintas regiones cerebrales, ayudando a que trabajen de forma unificada y concertada. En su estudio, las imágenes con tensor de difusión son una técnica idónea para detectar el grado de integridad de estas fibras. Actualmente, se les otorga un papel relevante en el desarrollo y patofisiología de diferentes trastornos del desarrollo, y éste ha sido el objetivo del presente trabajo. En la revisión de trastornos como el autismo, la dislexia o el trastorno por déficit de atención/hiperactividad, se ha encontrado una afectación clara de ciertas fibras, sobre todo en el fascículo longitudinal superior arqueado y la red temporoparietal (relacionados con la regulación de la conducta motora y atencional), el cuerpo calloso (que garantiza el intercambio eficaz y rápido de información entre los hemisferios cerebrales) y regiones del cíngulo (que guardarían relación con la cognición social y la autoconciencia (AU)

The white matter is the main connection between different regions of the brain and helps them to work in a unified, coordinated way. Diffusion tensor imaging is an ideal technique with which to study it in order to detect the degree of integrity of these fibres. Nowadays, they are considered to play a significant role in the development and pathophysiology of different developmental disorders, and the aim of this study was to examine this role. On reviewing disorders such as autism, dyslexia or attention deficit hyperactivity disorder, certain fibres were found to be clearly involved. This was especially the case of the (arcuate) superior longitudinal fasciculus and the temporal-parietal network (related with the regulation of motor and attentional behaviour), the corpus callosum (which ensures the efficient and swift exchange of information between the hemispheres of the brain) and cingulate regions (which would be related with social cognition and self-consciousness (AU)

Lack of the cerebral peduncle involvement in a series of adult supratentorial AVM: a diffusion tensor imaging study.

Congenital as arteriovenous malformation(AVM) is, most patients with AVM would be asymptomatic until adults. During the past 2 years, 23 cases of adult supratentorial AVM patients had DTI after admission. The region of interest was placed in the cerebral peduncle. Their FA value and fiber number was compared with those of cavernous malformation (CM) and tumor (glioma and meningioma). In the AVM group, there was no significant difference in FA of the cerebral peduncle (ipsilateral 0.758±0.055 versus contralateral 0.755±0.049; P>0.05) and fiber number (319.6±82.9 versus 304.7±89.1; P>0.05). In the CM group, FA of the cerebral peduncle on ipsilateral side (0.711±0.092) was significantly lower than that of contralateral side (0.768±0.043) (P<0.01). Similar result was in fiber number of the CM group (251±82.1 versus 307.3±77.0; P<0.05). In tumor group, FA of ipsilateral side (0.713±0.084) was lower than that of contralateral (0.751±0.052) without significant difference. There was no significant difference in fiber number between ipsilateral and contralateral sides in the tumor group (308.9±112.4 versus 287.9±62.4). Unlike non-AVM lesions (CM and tumor), FA value and fiber number of the ipsilateral cerebral peduncle is less influenced in the AVM group. The lack of the cerebral peduncle involvement indicates that there is plasticity of white matter in AVM.