Neuronal activity reorganization in motor cortex for successful locomotion after a lesion in the ventrolateral thalamus.

Thalamic stroke leads to ataxia if the cerebellum-receiving ventrolateral thalamus (VL) is affected. The compensation mechanisms for this deficit are not well understood, particularly the roles that single neurons and specific neuronal subpopulations outside the thalamus play in recovery. The goal of this study was to clarify neuronal mechanisms of the motor cortex involved in mitigation of ataxia during locomotion when part of the VL is inactivated or lesioned. In freely ambulating cats, we recorded the activity of neurons in layer V of the motor cortex as the cats walked on a flat surface and horizontally placed ladder. We first reversibly inactivated ∼10% of the VL unilaterally using glutamatergic transmission antagonist CNQX and analyzed how the activity of motor cortex reorganized to support successful locomotion. We next lesioned 50%-75% of the VL bilaterally using kainic acid and analyzed how the activity of motor cortex reorganized when locomotion recovered. When a small part of the VL was inactivated, the discharge rates of motor cortex neurons decreased, but otherwise the activity was near normal, and the cats walked fairly well. Individual neurons retained their ability to respond to the demand for accuracy during ladder locomotion; however, most changed their response. When the VL was lesioned, the cat walked normally on the flat surface but was ataxic on the ladder for several days after lesion. When ladder locomotion normalized, neuronal discharge rates on the ladder were normal, and the shoulder-related group was preferentially active during the stride's swing phase.NEW & NOTEWORTHY This is the first analysis of reorganization of the activity of single neurons and subpopulations of neurons related to the shoulder, elbow, or wrist, as well as fast- and slow-conducting pyramidal tract neurons in the motor cortex of animals walking before and after inactivation or lesion in the thalamus. The results offer unique insights into the mechanisms of spontaneous recovery after thalamic stroke, potentially providing guidance for new strategies to alleviate locomotor deficits after stroke.

Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia.

BACKGROUND: Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model. METHODS: Male C57BL/6 mice of 8-12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice. RESULTS: NPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice. CONCLUSIONS: These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

The right thalamic ventral posterolateral nucleus seems to be determinant for macrosomatognosia: a case report.

BACKGROUND: Macrosomatognosiais the illusory sensation of a substantially enlarged body part. This disorder of the body schema, also called "Alice in wonderland syndrome" is still poorly understood and requires careful documentation and analysis of cases. The patient presented here is unique owing to his unusual macrosomatognosia phenomenology, but also given the unreported localization of his most significant lesion in the right thalamus that allowed consistent anatomo-clinical analysis. CASE PRESENTATION: This 45-years old man presented mainly with long-lasting and quasi-delusional macrosomatognosia associated to sensory deficits, both involving the left upper-body, in the context of a right thalamic ischemic lesion most presumably located in the ventral posterolateral nucleus. Fine-grained probabilistic and deterministic tractography revealed the most eloquent targets of the lesion projections to be the ipsilateral precuneus, superior parietal lobule,but also the right primary somatosensory cortex and, to a lesser extent, the right primary motor cortex. Under stationary neurorehabilitation, the patient slowly improved his symptoms and could be discharged back home and, later on, partially return to work. CONCLUSION: We discuss deficient neural processing and integration of sensory inputs within the right ventral posterolateral nucleus lesion as possible mechanisms underlying macrosomatognosia in light of observed anatomo-clinical correlations. On the other hand, difficulty to classify this unique constellation of Alice in wonderland syndrome calls for an alternative taxonomy of cognitive and psychic aspects of illusory body-size perceptions.

Impaired glymphatic system in secondary degeneration areas after ischemic stroke in rats.

BACKGROUND: Pathomechanism of secondary degeneration in remote regions after ischemic stroke has not been totally clarified. Contrast-enhanced MRI with injecting Gd-DTPA in cisterna magna (CM) is regarded as an efficient method to measure glymphatic system function in brain. Our research aimed at evaluating glymphatic system changes in secondary degeneration areas by contrast-enhanced MRI. METHODS: Ischemic stroke was induced by left middle cerebral artery occlusion (MCAO) model. A total of 12 Sprague-Dawley rats were randomly divided into three groups: control group with sham operations (n=4), the group of acute phase (1 day after MCAO) (n=4), and the group of subacute phase (7 days after MCAO) (n=4). Contrast-enhanced MRI was performed in 1days or 7days after operations respectively. All rats received an intrathecal injection of Gd-DTPA (2µl/min, totally 20µl) and high-resolution 3D T1-weighted MRI for 6 h. The time course of the signal-to-noise ratio (SNR) in substantia Nigra (SN) and ventral thalamic nucleus (VTN) was evaluated between two hemispheres in all rats. RESULTS: In control group without ischemia, time-to-peak of SNR in SN was earlier than that in VTN. There were no differences of SNR between two hemispheres after intrathecal Gd-DTPA administration. In the group of acute phase, MRI revealed similar time course and time-to-peak of SNR between ipsilateral and contralateral VTN, while a tendency of higher SNR in ipsilateral SN than contralateral SN at 4h, 5h, 6h after Gd-DTPA injection. And time-to-peak of SNR was similar in bilateral SN. In the group of subacute phase, time-to-peak of SNR was similar in bilateral VTN, while longer in ipsilateral SN compared with contralateral side. In addition, SNR in T1WI in ipsilateral was significantly higher than SNR in contralateral SN and VTN at 5h (VTN, P= 0.003; SN, P=0.004) and 6h (VTN, P=0.015; SN, P=0.006) after Gd-DTPA injection. CONCLUSION: Glymphatic system was impaired in ipsilateral SN and VTN after ischemic stroke, which may contribute to neural degeneration.

Attack-related damage of thalamic nuclei in neuromyelitis optica spectrum disorders.

OBJECTIVES: In neuromyelitis optica spectrum disorders (NMOSD) thalamic damage is controversial, but thalamic nuclei were never studied separately. We aimed at assessing volume loss of thalamic nuclei in NMOSD. We hypothesised that only specific nuclei are damaged, by attacks affecting structures from which they receive afferences: the lateral geniculate nucleus (LGN), due to optic neuritis (ON) and the ventral posterior nucleus (VPN), due to myelitis. METHODS: Thirty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 50.1±14.1 years, 36 women, 25 with prior ON, 36 with prior myelitis) and 37 healthy controls (age: 47.8 ± 12.5 years, 32 women) were included in this cross-sectional study. Thalamic nuclei were assessed in magnetic resonance images, using a multi-atlas-based approach of automated segmentation. Retinal optical coherence tomography was also performed. RESULTS: Patients with ON showed smaller LGN volumes (181.6±44.2 mm3) compared with controls (198.3±49.4 mm3; B=-16.97, p=0.004) and to patients without ON (206.1±50 mm3 ; B=-23.74, p=0.001). LGN volume was associated with number of ON episodes (Rho=-0.536, p<0.001), peripapillary retinal nerve fibre layer thickness (B=0.70, p<0.001) and visual function (B=-0.01, p=0.002). Although VPN was not smaller in patients with myelitis (674.3±67.5 mm3) than controls (679.7±68.33; B=-7.36, p=0.594), we found reduced volumes in five patients with combined myelitis and brainstem attacks (B=-76.18, p=0.017). Volumes of entire thalamus and other nuclei were not smaller in patients than controls. CONCLUSION: These findings suggest attack-related anterograde degeneration rather than diffuse thalamic damage in NMOSD. They also support a potential role of LGN volume as an imaging marker of structural brain damage in these patients.

Functional characterization of a mouse model for central post-stroke pain.

BACKGROUND: Stroke patients often suffer from a central neuropathic pain syndrome called central post-stroke pain. This syndrome is characterized by evoked pain hypersensitivity as well as spontaneous, on-going pain in the body area affected by the stroke. Clinical evidence strongly suggests a dysfunction in central pain pathways as an important pathophysiological factor in the development of central post-stroke pain, but the exact underlying mechanisms remain poorly understood. To elucidate the underlying pathophysiology of central post-stroke pain, we generated a mouse model that is based on a unilateral stereotactic lesion of the thalamic ventral posterolateral nucleus, which typically causes central post-stroke pain in humans. RESULTS: Behavioral analysis showed that the sensory changes in our model are comparable to the sensory abnormalities observed in patients suffering from central post-stroke pain. Surprisingly, pharmacological inhibition of spinal and peripheral key components of the pain system had no effect on the induction or maintenance of the evoked hypersensitivity observed in our model. In contrast, microinjection of lidocaine into the thalamic lesion completely reversed injury-induced hypersensitivity. CONCLUSIONS: These results suggest that the evoked hypersensitivity observed in central post-stroke pain is causally linked to on-going neuronal activity in the lateral thalamus.

A pilot study of focused ultrasound thalamotomy for essential tremor.

BACKGROUND: Recent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor. METHODS: From February 2011 through December 2011, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. We recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from 0 to 160), hand subscore (primary outcome, ranging from 0 to 32), and disability subscore (ranging from 0 to 32), with higher scores indicating worse tremor. We assessed the patients' perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from 0 to 100%, with higher scores indicating greater perceived disability). RESULTS: Thermal ablation of the thalamic target occurred in all patients. Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesias in four patients. Scores for hand tremor improved from 20.4 at baseline to 5.2 at 12 months (P=0.001). Total tremor scores improved from 54.9 to 24.3 (P=0.001). Disability scores improved from 18.2 to 2.8 (P=0.001). Quality-of-life scores improved from 37% to 11% (P=0.001). CONCLUSIONS: In this pilot study, essential tremor improved in 15 patients treated with MRI-guided focused ultrasound thalamotomy. Large, randomized, controlled trials will be required to assess the procedure's efficacy and safety. (Funded by the Focused Ultrasound Surgery Foundation; ClinicalTrials.gov number, NCT01304758.).

Essential tremor is associated with disruption of functional connectivity in the ventral intermediate Nucleus--Motor Cortex--Cerebellum circuit.

The clinical benefits of targeting the ventral intermediate nucleus (VIM) for the treatment of tremors in essential tremor (ET) patients suggest that the VIM is a key hub in the network of tremor generation and propagation and that the VIM can be considered as a seed region to study the tremor network. However, little is known about the central tremor network in ET patients. Twenty-six ET patients and 26 matched healthy controls (HCs) were included in this study. After considering structural and head-motion factors and establishing the accuracy of our seed region, a VIM seed-based functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging (RS-fMRI) data was performed to characterize the VIM FC network in ET patients. We found that ET patients and HCs shared a similar VIM FC network that was generally consistent with the VIM anatomical connectivity network inferred from normal nonhuman primates and healthy humans. Compared with HCs, ET patients displayed VIM-related FC changes, primarily within the VIM-motor cortex (MC)-cerebellum (CBLM) circuit, which included decreased FC in the CBLM and increased FC in the MC. Importantly, tremor severity correlated with these FC changes. These findings provide the first evidence that the pathological tremors observed in ET patients might be based on a physiologically pre-existing VIM - MC - CBLM network and that disruption of FC in this physiological network is associated with ET. Further, these findings demonstrate a potential approach for elucidating the neural network mechanisms underlying this disease.

Central Nervous System-Toxic Lidocaine Concentrations Unmask L-Type Ca²âº Current-Mediated Action Potentials in Rat Thalamocortical Neurons: An In Vitro Mechanism of Action Study.

BACKGROUND: High systemic lidocaine concentrations exert well-known toxic effects on the central nervous system (CNS), including seizures, coma, and death. The underlying mechanisms are still largely obscure, and the actions of lidocaine on supraspinal neurons have received comparatively little study. We recently found that lidocaine at clinically neurotoxic concentrations increases excitability mediated by Na-independent, high-threshold (HT) action potential spikes in rat thalamocortical neurons. Our goal in this study was to characterize these spikes and test the hypothesis that they are generated by HT Ca currents, previously implicated in neurotoxicity. We also sought to identify and isolate the specific underlying subtype of Ca current. METHODS: We investigated the actions of lidocaine in the CNS-toxic concentration range (100 µM-1 mM) on ventrobasal thalamocortical neurons in rat brain slices in vitro, using whole-cell patch-clamp recordings aided by differential interference contrast infrared videomicroscopy. Drugs were bath applied; action potentials were generated using current clamp protocols, and underlying currents were identified and isolated with ion channel blockers and electrolyte substitution. RESULTS: Lidocaine (100 µM-1 mM) abolished Na-dependent tonic firing in all neurons tested (n = 46). However, in 39 of 46 (85%) neurons, lidocaine unmasked evoked HT action potentials with lower amplitudes and rates of de-/repolarization compared with control. These HT action potentials remained during the application of tetrodotoxin (600 nM), were blocked by Cd (50 µM), and disappeared after superfusion with an extracellular solution deprived of Ca. These features implied that the unmasked potentials were generated by high-voltage-activated Ca channels and not by Na channels. Application of the L-type Ca channel blocker, nifedipine (5 µM), completely blocked the HT potentials, whereas the N-type Ca channel blocker, ω-conotoxin GVIA (1 µM), had little effect. CONCLUSIONS: At clinically CNS-toxic concentrations, lidocaine unmasked in thalamocortical neurons evoked HT action potentials mediated by the L-type Ca current while substantially suppressing Na-dependent excitability. On the basis of the known role of an increase in intracellular Ca in the pathogenesis of local anesthetic neurotoxicity, this novel action represents a plausible contributing candidate mechanism for lidocaine's CNS toxicity in vivo.

Optimization of white-matter-nulled magnetization prepared rapid gradient echo (MP-RAGE) imaging.

PURPOSE: To optimize the white-matter-nulled (WMn) Magnetization Prepared Rapid Gradient Echo (MP-RAGE) sequence at 7 Tesla (T), with comparisons to 3T. METHODS: Optimal parameters for maximizing signal-to-noise ratio (SNR) efficiency were derived. The effect of flip angle and repetition time (TR) on image blurring was modeled using simulations and validated in vivo. A novel two-dimensional (2D) -centric radial fan beam (RFB) k-space segmentation scheme was used to shorten scan times and improve parallel imaging. Healthy subjects as well as patients with multiple sclerosis and tremor were scanned using the optimized protocols. RESULTS: Inversion repetition times (TS) of 4.5 s and 6 s were found to yield the highest SNR efficiency for WMn MP-RAGE at 3T and 7T, respectively. Blurring was more sensitive to flip in WMn than in CSFn MP-RAGE and relatively insensitive to TR for both regimes. The 2D RFB scheme had 19% and 47% higher thalamic SNR and SNR efficiency than the 1D centric scheme for WMn MP-RAGE. Compared with 3T, SNR and SNR efficiency were higher for the 7T WMn regime by 56% and 41%, respectively. MS lesions in the cortex and thalamus as well as thalamic subnuclei in tremor patients were clearly delineated using WMn MP-RAGE. CONCLUSION: Optimization and new view ordering enabled MP-RAGE imaging with 0.8-1 mm(3) isotropic spatial resolution in scan times of 5 min with whole brain coverage.

The non-motor complications in Parkinson's disease - what can we learn from animal models?

Sporadic Parkinson's disease is a widespread human disease that has never been reported in non-human vertebrates. The etiopathogenesis of the non-motor symptoms in the disease is not well understood and it is difficult to interpret the roles of affected neurotransmitters in currently available animal models. Most of the non-motor symptoms do not correlate with the stage of motor deficits and precede the development of motor symptoms by many years, before the permanent loss of dopaminergic neurons in the basal ganglia. The aim of this review is to briefly summarize the advantages and limitations of the well-recognized mammalian animal models with special regard to the non-motor complications of the prodromal and early stage Parkinson's disease.

Alterations in white matter fractional anisotropy in subsyndromal perimenopausal depression.

BACKGROUND: Subsyndromal depression (SSD) is considered as a predictor for future depressive disorders, however whether white matter abnormalities are involved in the high-susceptibility of women to depressive disorders during perimenopause is unknown. The purpose of this study was to investigate fractional anisotropy (FA) in the white matter of the whole brain in perimenopausal women with SSD using diffusion tensor imaging (DTI). METHODS: In a cross-sectional study, 24 perimenopausal women with SSD and 24 other age-, education-, and body mass index-matched healthy women underwent DTI. A voxel-based analysis was used to elucidate regional FA changes at a voxel threshold of p < 0.001 with an extent threshold of k > 127 voxels (p < 0.05, AlphaSim correction). Subsequently, correlation analyses were performed between mean FA values in significant brain regions and plasma estradiol level. RESULTS: Compared to healthy controls, women with SSD exhibited significantly lower FA values in the left insula, while higher FA values were observed in the left ventral lateral thalamus and left and right brainstem in the midbrain. In subjects with SSD, the mean FA value in the left insula was positively correlated to plasma estradiol levels (r = 0.453, p = 0.026) (uncorrected). CONCLUSIONS: Our findings indicate altered microstructures in white matter of the insula and subcortical regions may be associated with the high susceptibility of perimenopausal women to depressive disorders. Estrogen may modulate the white matter microstructure of the insula.

Thalamic sensory strokes with and without pain: differences in lesion patterns in the ventral posterior thalamus.

OBJECTIVE: Vascular lesions of the posterolateral thalamus typically result in a somatosensory syndrome in which some patients develop central neuropathic post-stroke pain (CPSP). Damage to the spinothalamic tract terminus is assumed to be a prerequisite for thalamic CPSP. At the nuclear level, it remains a matter of debate whether the ventral posterolateral nucleus (VPL) or the posterior portion of the ventral medial nucleus (VMpo) constitutes the decisive lesion site. The hypothesis of the study was that lesion location in thalamic CPSP patients differs from that in thalamic stroke patients without pain, and the aim was to identify whether this difference comprises the VPL and/or the VMpo. DESIGN: 30 patients with chronic thalamic stroke and a persistent contralateral somatosensory syndrome were examined. CPSP patients (n=18) were compared with non-pain control patients. By coregistration of a digitised thalamic atlas with T1 weighted MR images, lesion clusters were allocated to the thalamic nuclei. RESULTS: VPL was affected in both groups, but CPSP lesion clusters comprised the more posterior, inferior and lateral parts of the VPL compared with controls. Additional partial involvement of the VMpo was seen in only three pain patients. In three other pain patients, lesions involved neither the VPL nor the VMpo, but mainly affected the anterior pulvinar. CONCLUSION: This study specifies the role of the VPL in thalamic CPSP and shows that the posterolateratal and inferior parts in particular are critically lesioned in pain patients. In this thalamic subregion, afferents of the spinothalamic tract are known to terminate. In contrast, the data do not support a pivotal impact of the VMpo on thalamic CPSP.

Ensemble encoding of nociceptive stimulus intensity in the rat medial and lateral pain systems.

BACKGROUND: The ability to encode noxious stimulus intensity is essential for the neural processing of pain perception. It is well accepted that the intensity information is transmitted within both sensory and affective pathways. However, it remains unclear what the encoding patterns are in the thalamocortical brain regions, and whether the dual pain systems share similar responsibility in intensity coding. RESULTS: Multichannel single-unit recordings were used to investigate the activity of individual neurons and neuronal ensembles in the rat brain following the application of noxious laser stimuli of increasing intensity to the hindpaw. Four brain regions were monitored, including two within the lateral sensory pain pathway, namely, the ventral posterior lateral thalamic nuclei and the primary somatosensory cortex, and two in the medial pathway, namely, the medial dorsal thalamic nuclei and the anterior cingulate cortex. Neuron number, firing rate, and ensemble spike count codings were examined in this study. Our results showed that the noxious laser stimulation evoked double-peak responses in all recorded brain regions. Significant correlations were found between the laser intensity and the number of responsive neurons, the firing rates, as well as the mass spike counts (MSCs). MSC coding was generally more efficient than the other two methods. Moreover, the coding capacities of neurons in the two pathways were comparable. CONCLUSION: This study demonstrated the collective contribution of medial and lateral pathway neurons to the noxious intensity coding. Additionally, we provide evidence that ensemble spike count may be the most reliable method for coding pain intensity in the brain.

Lesions of the cerebello-thalamic tract rather than the ventral intermediate nucleus determine the outcome of focused ultrasound therapy in essential tremor: A 3T and 7T MRI-study.

INTRODUCTION: The ventral intermediate nucleus of the thalamus (VIM) is an important relay station receiving cerebellar and pallidal fiber tracts. Data on structural visualization of the VIM however is limited and uncertainty prevails to what extent lesional approaches to treat tremor affect the VIM itself or passing tracts. The aim of the study was to analyze the localization of individual lesions with respect to the VIM and the cerebello-thalamic tract (CTT). METHODS: We employed ultrahigh resolution (7 Tesla) MRI to delineate the VIM and performed 3 T-DTI-imaging pre- and post-interventional in seven ET patients undergoing transcranial magnetic resonance guided focused ultrasound (tcMRgFUS). Tremor improvement was measured using a modified subscore of the Clinical Rating Scale for Tremor. RESULTS: All subjects showed substantial tremor improvement (88.5%, range 80.7%-94,8%) after tcMRgFUS. We found only a minor overlap of the lesions with the VIM (4%, range 1%-7%) but a larger overlap with the CTT (43%, range 23%-60%) in all subjects. CONCLUSIONS: Lesions within the CTT rather than the VIM seem to drive the tremorlytic response and clinical improvement in tcMRgFUS.

Long-term deep brain stimulation for essential tremor: 12-year clinicopathologic follow-up.

We describe the clinical course and postmortem pathological findings in a patient with essential tremor (ET) treated with deep brain stimulation (DBS) for 12 years. This 75 year old woman had a 13-year history of progressive ET prior to implantation of bilateral quadripolar DBS electrodes in the region of her ventral intermediate thalamic nuclei in 1996, producing immediate relief of arm tremor. Histopathological examination of the brain, performed 12 years after the initial implantation, demonstrated electrode catheter tracts rimmed by 20-25 micron fibrous sheaths, with multinucleated giant cells and reactive gliosis. Lymphocytic infiltration was seen by L26 immunoreactivity with CD3 (T cells) staining predominating over CD20 (B cells). Cerebellar axonal spheroids and Purkinje cell loss were found. The minimal foreign body reaction and gliosis around the electrodes 12 years after implantation supports the long-term safety of DBS. The case represents the longest reported follow-up with autopsy examination after DBS and confirmed histological changes associated with ET.

Gudden's ventral tegmental nucleus is vital for memory: re-evaluating diencephalic inputs for amnesia.

Mammillary body atrophy is present in a number of neurological conditions and recent clinical findings highlight the importance of these nuclei for memory. While most accounts of diencephalic amnesia emphasize the functional importance of the hippocampal projections to the mammillary bodies, the present study tested the importance of the other major input to the mammillary bodies, the projections from the ventral tegmental nucleus of Gudden (VTNg). Although the VTNg, and its projections to the mammillary bodies, is present across species, the size and location of this structure has made it an extremely difficult structure to assess in primates. The effects of selective, neurotoxic lesions of the VTNg were, therefore, assessed in rats. The animals with these lesions were impaired on a series of spatial learning tasks, namely delayed-matching-to-place in the water maze, T-maze alternation and working memory in the radial arm maze. Normal performance on these tasks is dependent on those brain structures (e.g. hippocampus and mammillary bodies) that are now assumed to cause anterograde amnesia when damaged in humans. In contrast, the same rats with ventral tegmental nucleus lesions performed normally on two control tasks: the acquisition and subsequent reversal of an egocentric discrimination task and a visually cued task in the water maze. This study provides the first clear evidence that the VTNg is critical for memory, and consequently indicates that diencephalic-hippocampal models of memory should be extended to incorporate the limbic midbrain.

Brain Atrophy Following Deep Brain Stimulation: Management of a Moving Target.

Clinical vignette: A 51-year-old man with essential tremor (ET) had bilateral ventralis intermedius nucleus deep brain stimulation (VIM-DBS) placed to address refractory tremor. Despite well-placed DBS leads and adequate tremor response, he subsequently experienced worsening. Re-programming of the device and reconfirming the electrical thresholds for benefits and side effects were both performed. Six years following DBS implantation, repeat imaging revealed brain atrophy and a measured lead position change with a coincident change in clinical response. Clinical dilemma: What do we know about brain atrophy affecting lead placement and long-term DBS effectiveness? What are the potential strategies to combat narrowed therapeutic thresholds and to maximize DBS therapeutic benefit? Clinical solution: Decreasing the electrical field of stimulation and programming in a bipolar configuration are strategies to provide symptomatic tremor control and to minimize stimulation-induced side effects. Gaps in knowledge: Currently, effects of brain atrophy, and factors underpinning emergence of side effects and/or loss of benefit in chronic VIM-DBS remain largely unexplored.

Attenuation of secondary damage and Aß deposits in the ipsilateral thalamus of dMCAO rats through reduction of cathepsin B by bis(propyl)-cognitin, a multifunctional dimer.

Delayed secondary degeneration in the non-ischemic sites such as ipsilateral thalamus would occur after cortical infarction. Hence, alleviating secondary damage is considered to be a promising novel target for acute stroke therapy. In the current study, the neuroprotective effects of bis(propyl)-cognitin (B3C), a multifunctional dimer, against secondary damage in the VPN of ipsilateral thalamus were investigated in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. It was found that B3C (0.5 and 1 mg/kg, ip) effectively improved neurological function of rats at day 7 and day 14 after dMCAO. Additionally, the treatment with B3C alleviated neuronal loss and gliosis in ipsilateral VPN after dMCAO, as evidenced by the higher immunoreactivity of neuron-specific nuclear-binding protein (NeuN) as well as lower immunostaining intensity of glial fibrillary acidic protein (GFAP) and cluster of differentiation 68 (CD68). Most encouragingly, immunohistochemistry and western blotting further revealed that B3C treatment greatly reduced Aß deposits and cathepsin B expression in the VPN of ipsilateral thalamus at day 7 and day 14 after dMCAO. In parallel, we demonstrated herein that the neuroprotective effects of B3C in dMCAO model were similar to L-3-trans-(Propyl-carbamoyloxirane-2-carbonyl)- L-isoleucyl-l-proline methyl ester (CA-074Me), a specific inhibitor of cathepsin B, suggesting that B3C attenuated secondary damage and Aß deposits in the VPN of ipsilateral thalamus after dMCAO possibly through the reduction of cathepsin B. These findings taken together provide novel molecular sights into the potential application of B3C for the treatment of secondary degeneration after cortical infarction.

Anterior hippocampus in schizophrenia pathogenesis: molecular evidence from a proteome study.

OBJECTIVE: The purpose of the present study was to identify differentially expressed proteins in the anterior and posterior hippocampus of brains of schizophrenia patients compared to neurologically healthy controls. METHOD: Proteins extracted from fresh frozen post-mortem posterior and anterior hippocampus for nine schizophrenia and nine control individuals, and seven schizophrenia and seven control individuals, respectively, were screened for differential expression using 2-D gel electrophoresis and mass spectrometry. RESULTS: A significantly larger number of protein spots were differentially expressed in the anterior (n = 43) compared to the posterior (n = 16) hippocampus, representing 34 and 14 unique proteins, respectively. These proteins are involved in cytoskeleton structure and function, neurotransmission and mitochondrial function. CONCLUSION: Based on the aberrant protein expression profiles, the anterior hippocampus appears to be more involved in schizophrenia pathogenesis than the posterior hippocampus. Furthermore, consistent with previous findings, we found molecular evidence to support abnormal neuronal cytoarchitecture and function, neurotransmission and mitochondrial function in the schizophrenia hippocampus.