Oxytocin shapes the neural circuitry of trust and trust adaptation in humans.

Trust and betrayal of trust are ubiquitous in human societies. Recent behavioral evidence shows that the neuropeptide oxytocin increases trust among humans, thus offering a unique chance of gaining a deeper understanding of the neural mechanisms underlying trust and the adaptation to breach of trust. We examined the neural circuitry of trusting behavior by combining the intranasal, double-blind, administration of oxytocin with fMRI. We find that subjects in the oxytocin group show no change in their trusting behavior after they learned that their trust had been breached several times while subjects receiving placebo decrease their trust. This difference in trust adaptation is associated with a specific reduction in activation in the amygdala, the midbrain regions, and the dorsal striatum in subjects receiving oxytocin, suggesting that neural systems mediating fear processing (amygdala and midbrain regions) and behavioral adaptations to feedback information (dorsal striatum) modulate oxytocin's effect on trust. These findings may help to develop deeper insights into mental disorders such as social phobia and autism, which are characterized by persistent fear or avoidance of social interactions.

Preoperative MRI findings and functional outcome after selective dorsal rhizotomy in children with bilateral spasticity

PURPOSE: To identify MRI characteristics that may predict the functional effect of selective dorsal rhizotomy (SDR) in children with bilateral spastic paresis. METHODS: We performed SDR in a group of 36 patients. The gross motor functioning measure-66 (GMFM-66) was applied before and after SDR. Available cerebral MRIs were retrospectively classified into three diagnostic groups: periventricular leucomalacia (PVL; n = 10), hydrocephalus (n = 2), and normal (n = 6). In patients with PVL, we scored the severity of the MR abnormalities. We compared the changes in the GMFM-66 after SDR in the diagnostic groups. In patients with PVL, we correlated the severity of the MR abnormalities with the changes in the GMFM-66. RESULTS: The mean follow-up period was 5 years and 4 months (range, 1 year and 1 month to 9 years). The best improvement in gross motor function was observed in patients with normal MRI, and the slightest improvement was observed in patients with hydrocephalus. The severity of the PVL did correlate with the GMFM-66 score before SDR but not with the functional effect of SDR. CONCLUSION: We conclude that with respect to gross motor skills, the improvements after SDR are good in patients with no MRI abnormalities. In the patients with hydrocephalus, the improvements after SDR were insignificant. In patients with PVL, the improvements were intermediate and did not correlate with the degree of PVL.

Intraneuronal angiotensinergic system in rat and human dorsal root ganglia

To elucidate the local formation of angiotensin II (Ang II) in the neurons of sensory dorsal root ganglia (DRG), we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of protein renin, Ang II, Substance P and calcitonin gene-related peptide (CGRP) in the rat and human thoracic DRG. Quantitative real time PCR (qRT-PCR) studies revealed that rat DRG expressed substantial amounts of Ang-N- and ACE mRNA, while renin mRNA as well as the protein renin were untraceable. Cathepsin D-mRNA and cathepsin D-protein were detected in the rat DRG indicating the possibility of existence of pathways alternative to renin for Ang I formation. Angiotensin peptides were successfully detected with high performance liquid chromatography and radioimmunoassay in human DRG extracts. In situ hybridization in rat DRG confirmed additionally expression of Ang-N mRNA in the cytoplasm of numerous neurons. Intracellular Ang II staining could be shown in number of neurons and their processes in both the rat and human DRG. Interestingly we observed neuronal processes with angiotensinergic synapses en passant, colocalized with synaptophysin, within the DRG. In the DRG, we also identified by qRT-PCR, expression of Ang II receptor AT(1A) and AT(2)-mRNA while AT(1B)-mRNA was not traceable. In some neurons Substance P and CGRP were found colocalized with Ang II. The intracellular localization and colocalization of Ang II with Substance P and CGRP in the DRG neurons may indicate a participation and function of Ang II in the regulation of nociception. In conclusion, these results suggest that Ang II may be produced locally in the neurons of rat and human DRG and act as a neurotransmitter.

Effect of selective dorsal rhizotomy on gait in children with bilateral spastic paresis: kinematic and EMG-pattern changes

Selective dorsal rhizotomy (SDR) is an effective treatment for reducing spasticity and improving gait in children with spastic cerebral palsy. Data concerning muscle activity changes after SDR treatment are limited.

Synaptic regulation of spike firing in interneurons of the striatum in vivo

The striatum, the major input nucleus of the basal ganglia, is numerically dominated by a single class of principal neurons, the GABAergic spiny projection neuron (SPN) that has been extensively studied both in vitro and in vivo. Much less is known about the sparsely distributed interneurons, principally the cholinergic interneuron (CIN) and the GABAergic fast-spiking interneuron (FSI). Here, we summarize results from two recent studies on these interneurons where we used in vivo intracellular recording techniques in urethane-anaesthetized rats (Schulz et al., J Neurosci 31[31], 2011; J Physiol, in press). Interneurons were identified by their characteristic responses to intracellular current steps and spike waveforms. Spontaneous spiking contained a high proportion (~45%) of short inter-spike intervals (ISI) of <30 ms in FSIs, but virtually none in CINs. Spiking patterns in CINs covered a broad spectrum ranging from regular tonic spiking to phasic activity despite very similar unimodal membrane potential distributions across neurons. In general, phasic spiking activity occurred in phase with the slow ECoG waves, whereas CINs exhibiting tonic regular spiking were little affected by afferent network activity. In contrast, FSIs exhibited transitions between Down and Up states very similar to SPNs. Compared to SPNs, the FSI Up state membrane potential was noisier and power spectra exhibited significantly larger power at frequencies in the gamma range (55-95 Hz). Cortical-evoked inputs had faster dynamics in FSIs than SPNs and the membrane potential preceding spontaneous spike discharge exhibited short and steep trajectories, suggesting that fast input components controlled spike output in FSIs. Intrinsic resonance mechanisms may have further enhanced the sensitivity of FSIs to fast oscillatory inputs. Induction of an activated ECoG state by local ejection of bicuculline into the superior colliculus, resulted in increased spike frequency in both interneuron classes without changing the overall distribution of ISIs. This manipulation also made CINs responsive to a light flashed into the contralateral eye. Typically, the response consisted of an excitation at short latency followed by a pause in spike firing, via an underlying depolarization-hyperpolarization membrane sequence. These results highlight the differential sensitivity of striatal interneurons to afferent synaptic signals and support a model where CINs modulate the striatal network in response to salient sensory bottom-up signals, while FSIs serve gating of top-down signals from the cortex during action selection and reward-related learning.

Long-term outcome and adverse effects of selective dorsal rhizotomy in children with cerebral palsy: a systematic review

To assess the long-term outcome and adverse events of selective dorsal rhizotomy (SDR) in children with spastic cerebral palsy (CP).

Dorsal rather than ventral visual pathways discriminate freezing status in Parkinson's disease

BACKGROUND: Although visuospatial deficits have been linked with freezing of gait (FOG) in Parkinson's disease (PD), the specific effects of dorsal and ventral visual pathway dysfunction on FOG is not well understood. METHOD: We assessed visuospatial function in FOG using an angle discrimination test (dorsal visual pathway bias) and overlapping figure test (ventral visual pathway bias), and recorded overall response time, mean fixation duration and dwell time. Covariate analysis was conducted controlling for disease duration, motor severity, contrast sensitivity and attention with Bonferroni adjustments for multiple comparisons. RESULTS: Twenty seven people with FOG, 27 people without FOG and 24 controls were assessed. Average fixation duration during angle discrimination distinguished freezing status: [F (1, 43) = 4.77 p < 0.05] (1-way ANCOVA). CONCLUSION: Results indicate a preferential dysfunction of dorsal occipito-parietal pathways in FOG, independent of disease severity, attentional deficit, and contrast sensitivity.

Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain

Neuronal hyperexcitability following peripheral nerve lesions may stem from altered activity of voltage-gated sodium channels (VGSCs), which gives rise to allodynia or hyperalgesia. In vitro, the ubiquitin ligase Nedd4-2 is a negative regulator of VGSC α-subunits (Na(v)), in particular Na(v)1.7, a key actor in nociceptor excitability. We therefore studied Nedd4-2 in rat nociceptors, its co-expression with Na(v)1.7 and Na(v)1.8, and its regulation in pathology. Adult rats were submitted to the spared nerve injury (SNI) model of neuropathic pain or injected with complete Freund's adjuvant (CFA), a model of inflammatory pain. L4 dorsal root ganglia (DRG) were analyzed in sham-operated animals, seven days after SNI and 48 h after CFA with immunofluorescence and Western blot. We observed Nedd4-2 expression in almost 50% of DRG neurons, mostly small and medium-sized. A preponderant localization is found in the non-peptidergic sub-population. Additionally, 55.7 ± 2.7% and 55.0 ± 3.6% of Nedd4-2-positive cells are co-labeled with Na(v)1.7 and Na(v)1.8 respectively. SNI significantly decreases the proportion of Nedd4-2-positive neurons from 45.9 ± 1.9% to 33.5 ± 0.7% (p<0.01) and the total Nedd4-2 protein to 44% ± 0.13% of its basal level (p<0.01, n=4 animals in each group, mean ± SEM). In contrast, no change in Nedd4-2 was found after peripheral inflammation induced by CFA. These results indicate that Nedd4-2 is present in nociceptive neurons, is downregulated after peripheral nerve injury, and might therefore contribute to the dysregulation of Na(v)s involved in the hyperexcitability associated with peripheral nerve injuries.

Role of calcium-independent phospholipase A2 in cortex striatum thalamus cortex circuitry-enzyme inhibition causes vacuous chewing movements in rats

RATIONALE: High levels of calcium independent phospholipase A2 (iPLA2) are present in certain regions of the brain, including the cerebral cortex, striatum, and cerebellum (Ong et al. 2005). OBJECTIVES: The present study was carried out to elucidate a possible role of the enzyme in the motor system. METHODS: The selective iPLA2 inhibitor bromoenol lactone (BEL), the nonselective PLA2 inhibitor methyl arachidonyl fluorophosphonate (MAFP), and an antisense oligonucleotide were used to interfere with iPLA2 activity in various components of the motor system. Control animals received injections of carrier (phosphate buffered saline, PBS) at the same locations. The number of vacuous chewing movements (VCM) was counted from 1 to 14 days after injection. RESULTS: Rats that received BEL and high-dose MAFP injections in the striatum, thalamus, and motor cortex, but not the cerebellum, showed significant increase in VCM, compared to those injected with PBS at these locations. BEL-induced VCM were blocked by intramuscular injections of the anticholinergic drug, benztropine. Increased VCM was also observed after intrastriatal injection of antisense oligonucleotide to iPLA2. The latter caused a decrease in striatal iPLA2 levels, confirming a role of decreased enzyme activity in the appearance of VCM. CONCLUSIONS: These results suggest an important role for iPLA2 in the cortex-striatum-thalamus-cortex circuitry. It is postulated that VCM induced by iPLA2 inhibition may be a model of human parkinsonian tremor.

Effectiveness of selective dorsal rhizotomy in 2 patients with progressive spasticity due to neurodegenerative disease

Selective dorsal rhizotomy at the lumbar level is a neurosurgical procedure, which reduces spasticity in the legs. Its effect has mainly been studied in children with spastic cerebral palsy. Little is known about the outcome of selective dorsal rhizotomy in patients with neurodegenerative disorders. We report the clinical course after selective dorsal rhizotomy in 2 patients with progressive spasticity. Leg spasticity was effectively and persistently reduced in both patients, facilitating care and improving sitting comfort. However, spasticity of the arms and other motor disturbances, such as spontaneous extension spasms and the ataxia, increased gradually in time. Selective dorsal rhizotomy leads to a disappearance of leg spasticity in patients with a neurodegenerative disease. Other motor signs are not influenced and may increase due to the progressive nature of the underlying disease.

Dynamic repair of scapholunate dissociation with dorsal extensor carpi radialis longus tenodesis

This study investigates the results of a technique using an extensor carpi radialis longus (ECRL) tenodesis for symptomatic scapholunate instability. Symptomatic scapholunate instability has been corrected so far either by limited wrist fusion or by various techniques of soft tissue repair. Limited wrist fusion greatly reduces wrist motion and increases the probability of osteoarthritis in the remaining mobile wrist segments. On the other hand, most types of soft tissue repair are technically difficult to perform and have disappointing results due to the inherent laxity. The presented dynamic approach was used in 20 wrists of 19 patients with static scapholunate instability. Preoperative evaluation included in all patients clinical examination, radiologic evaluation, and arthroscopy for establishing the diagnosis of static scapholunate instability. The technique involves the fixation of the ECRL tendon on the dorsal aspect of the scaphoid by means of a cancellous screw and a special washer. Dynamic ECRL tenodesis of the scaphoid is a safe and simple procedure that enhances the extension forces on the scaphoid in all wrist positions. The results of this preliminary report in 20 wrists showed dynamic ECRL tenodesis to be an effective treatment option for treating symptomatic static scapholunate instability.

Lateralization of dynorphin gene expression in the rat striatum

Hemispheric lateralization is well known in the cerebral cortex, but not in subcortical structures like basal ganglia. The goal of our study was to determine whether lateralization was present in the direct and indirect striatal pathways. We studied gene expression in the striatum of healthy rats, which was divided into two sectors, medial and lateral. Dynorphin (DYN) and enkephalin (ENK) mRNA were analyzed as markers of the direct and indirect striatal pathways, respectively and glutamic acid decarboxylase (GAD) mRNA was analyzed as a marker of all medium spiny neurons. DYN and GAD mRNA expression was higher on the left hemisphere in the medial sector of the striatum, but not in the lateral one. We did not observe any difference between sides with ENK mRNA expression. We suggest the presence of a lateralization in the medial striatum, which is specific for the direct striatal pathway.

Adenosine A2A receptor gene expression in the normal striatum and after 6-OH-dopamine lesion

Adenosine A2A receptors are present on enkephalinergic medium sized striatal neurons in the rat and have an important function in the modulation of striatal output. In order to establish more accurately whether adenosine transmission is a generalized phenomenon in mammalian striatum we compared the A2A R expression in the mouse, rat, cat and human striatum. Secondly we compared the modulation of enkephalin gene expression and A2A receptor gene expression in rat striatal neurons after 6-OH-dopamine lesion of the substantia nigra. Hybridization histochemistry was performed with a 35S-labelled radioactive oligonucleotide probe. The results showed high expression of A2A adenosine receptor genes only in the medium-sized cells of the striatum in all examined species. In the rat striatum, expression of A2A receptors was not significantly altered after lesion of the dopaminergic pathways with 6-OH-dopamine even though enkephalin gene expression was up-regulated. The absence of a change in A2A receptor gene expression after 6-OH-dopamine treatment speaks against a dependency on dopaminergic innervation. The maintained inhibitory function of A2A R on motor activity in spite of dopamine depletion could be partly responsible for the depression of locomotor activity observed in basal ganglia disorders such as Parkinson's disease.