Dysfunction of the glutamatergic photoreceptor synapse in the P301S mouse model of tauopathy.

Tauopathies, including Alzheimer's disease, are characterized by retinal ganglion cell loss associated with amyloid and phosphorylated tau deposits. We investigated the functional impact of these histopathological alterations in the murine P301S model of tauopathy. Visual impairments were demonstrated by a decrease in visual acuity already detectable at 6 months, the onset of disease. Visual signals to the cortex and retina were delayed at 6 and 9 months, respectively. Surprisingly, the retinal output signal was delayed at the light onset and advanced at the light offset. This antagonistic effect, due to a dysfunction of the cone photoreceptor synapse, was associated with changes in the expression of the vesicular glutamate transporter and a microglial reaction. This dysfunction of retinal glutamatergic synapses suggests a novel interpretation for visual deficits in tauopathies and it highlights the potential value of the retina for the diagnostic assessment and the evaluation of therapies in Alzheimer's disease and other tauopathies.

Functional ultrasound imaging of the spreading activity following optogenetic stimulation of the rat visual cortex.

Optogenetics has revolutionized neurosciences by allowing fine control of neuronal activity. An important aspect for this control is assessing the activation and/or adjusting the stimulation, which requires imaging the entire volume of optogenetically-induced neuronal activity. An ideal technique for this aim is fUS imaging, which allows one to generate brain-wide activation maps with submesoscopic spatial resolution. However, optical stimulation of the brain with blue light might lead to non-specific activations at high irradiances. fUS imaging of optogenetic activations can be obtained at these wavelengths using lower light power (< 2mW) but it limits the depth of directly activatable neurons from the cortical surface. Our main goal was to report that we can detect specific optogenetic activations in V1 even in deep layers following stimulation at the cortical surface. Here, we show the possibility to detect deep optogenetic activations in anesthetized rats expressing the red-shifted opsin ChrimsonR in V1 using fUS imaging. We demonstrate the optogenetic specificity of these activations and their neuronal origin with electrophysiological recordings. Finally, we show that the optogenetic response initiated in V1 spreads to downstream (LGN) and upstream (V2) visual areas.

Post-stroke fatigue: how it relates to motor fatigability and other modifiable factors in people with chronic stroke.

Post-stroke fatigue (PSF) is a common symptom associated with disability and decreased quality of life. Distinction can be made between perceived fatigue and fatigability. The first aim of this study was to evaluate the prevalence of perceived fatigue and fatigability amongst patients with chronic stroke and to explore how these two parameters relate. The second aim was to study the relationship between modifiable factors (sleep disorders, anxiety, depression and activities of daily living) and fatigue in this population. Sixty-two patients with chronic stroke (> 6 months) were included. Perceived fatigue was evaluated using the Fatigue Severity Scale (FSS). Motor fatigability was assessed with the percent change in meters walked from first to last minute of the 6-min Walk Test and an isometric muscular fatigability test. Subjects also completed self-report questionnaires assessing anxiety and depression (Hospital Anxiety and Depression Scale-HADS), sleep quality (Pittsburgh Sleep Quality Index-PSQI) and activity limitations (ACTIVLIM-stroke). Seventy-one percent of participants presented PSF. There was no correlation between the FSS and motor fatigability. FSS significantly correlated with HADS-Anxiety (ρ = 0.53, P < 0.001), HADS-depression (ρ = 0.63, P < 0.001), PSQI (ρ = 0.51, P < 0.001) and ACTIVLIM (ρ = - 0.30, P < 0.05). A linear regression model showed that the HADS-Depression, the PSQI and the ACTIVLIM explained 46% of the variance of the FSS. A high proportion of chronic stroke patients presents PSF, with no relation between their fatigue and fatigability. Perceived fatigue is associated with potentially modifiable factors: anxious and depressive symptoms, poor sleep quality and activity limitations. Registered at ClinicalTrials.gov (NCT04277234) (21/02/2019).

Diffusion through Nanopores in Connected Lipid Bilayer Networks.

A biomimetic model of cell-cell communication was developed to probe the passive molecular transport across ion channels inserted in synthetic lipid bilayers formed between contacting droplets arranged in a linear array. Diffusion of a fluorescent probe across the array was measured for different pore concentrations. The diffusion characteristic timescale is found to vary nonlinearly with the pore concentration. Our measurements are successfully modeled by a continuous time random walk description whose waiting time is the first exit time from a droplet through a cluster of pores. The size of the cluster of pores is found to increase with their concentration. Our results provide a direct link between the mesoscopic permeation properties and the microscopic characteristics of the pores, such as their number, size, and spatial arrangement.

Itch and the brain.

The sensation of itch - defined as unpleasant sensation inducing the urge to scratch - is processed by a network of different brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational patterns. Patients with atopic eczema show different activation patterns and kinetics compared to healthy volunteers. This review summarizes current studies investigating itch in the brain.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes.

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.

[Studies on cerebral processing of pain using functional imaging : Somatosensory, emotional, cognitive, autonomic and motor aspects]. / Untersuchungen zur zerebralen Verarbeitung von Schmerzen mit funktioneller Bildgebung : Somatosensorische, affektive, kognitive, vegetative und motorische Aspekte.

Functional neuroimaging methods such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) provide fascinating insights into the cerebral processing of pain. Neuroimaging studies have shown that no clearly defined "pain centre" exists. Rather, an entire network of brain regions is involved in the processing of nociceptive information, which leads to the subjective impression of "pain". Sophisticated study designs nowadays permit the characterisation of different components of pain processing. In this review, we summarise neuroimaging studies, which contributed to the characterisation of these different aspects of cerebral pain processing, such as somatosensory (discrimination of different stimulus modalities, noxious vs non-noxious, summation), emotional, cognitive (attention, anticipation, distraction), vegetative (homeostasis) and motor aspects.

The mu-opioid receptor agonist remifentanil induces acute dysphoria irrespective of its analgesic properties.

Mu-opioidergic agonists are believed to induce euphoria, whereas kappa-agonists are thought to lead to dysphoria. Our study investigated mood effects of remifentanil, a mu-receptor opioid agonist, in healthy male volunteers. Moreover, we examined interactions between mood and pain. Three conditions were investigated in 21 volunteers: saline, 0.05 and 0.15 microg kg(-1) min(- 1) remifentanil. Each condition was investigated during non-painful heat and during painful heat stimulation. Mood was measured with the von Zerssen's mood scale (Bf-S score) and pain intensity using a Visual Analogue Scale (VAS). High Bf-S scores are reflecting discontent and dysphoria. Changes were tested for significance using a linear mixed model approach. Remifentanil significantly increased Bf-S scores during painful heat (+91.4%), indicating a negative mood effect, although it reduced VAS scores of painful heat intensity (-49.0%). The type of sensory stimulation (non-painful versus painful) had no effect on mood. There was no interaction between remifentanil dose and type of stimulation. Our results provide evidence for negative mood effects of remifentanil. These effects occur with and without pain. Taken into account that remifentanil reduces pain, one could have expected analgesia-related amelioration of mood instead. In clinical practice, these remifentanil effects should be considered and a comedication might be advisable.

Temperature modulated histamine-itch in lesional and nonlesional skin in atopic eczema - a combined psychophysical and neuroimaging study.

BACKGROUND: Itch is the major symptom of many allergic diseases; yet it is still difficult to measure objectively. The aim of this study was to use an evaluated itch stimulus model in lesional (LS) and nonlesional (NLS) atopic eczema (AE) skin and to characterize cerebral responses using functional magnetic resonance imaging (fMRI). METHODS: Thermal modulation was performed on a histamine stimulus in randomized order on LS or NLS in rapid alternating order from 32 degrees C (warm) to 25 degrees C (cold). Subjective itch ratings were recorded. Additionally, fMRI measurements were used to analyze the cerebral processing (n = 13). Healthy skin (HS) of age-matched volunteers served as control (n = 9). RESULTS: Mean VAS itch intensity was significantly (P < 0.0001) higher during the relative cold [55.2 +/- 8.3% (LS); 48.6 +/- 8.2% (NLS)] compared to the relative warm blocks [36.0 +/- 7.3% (LS); 33.7 +/- 7.6% (NLS)]. Compared to HS, the itch response was delayed in LS and NLS. Itch intensity was perceived highest in LS, followed by NLS and HS. For NLS, fMRI revealed at the beginning of the itch provocation a cerebral deactivation pattern in itch processing structures (thalamus, prefrontal, cingulate, insular, somatosensory and motor cortex). During the course of stimulation, the cerebral deactivation was reduced with time and instead an activation of the basal ganglia occurred. In contrast LS showed an activation instead of deactivation pattern already at the beginning of the stimulation in the above mentioned structures. CONCLUSIONS: Moderate short-term temperature modulation led to a reproducible, significant enhancement of histamine-induced itch with the strongest effect in LS. The differences in itch perception and itch kinetics between healthy volunteers and NLS in patients point towards an ongoing central inhibitory activity patients with AE, especially at the beginning of the itch provocation.

Voxel-based morphometry in individual patients: a pilot study in early Huntington disease.

BACKGROUND AND PURPOSE: Voxel-based morphometry (VBM) has proved a powerful method to detect subtle changes of gray matter (GM) at the group level but the role of VBM for the detection of GM changes in single subjects, especially in those with suspected neurodegenerative disorder, remains uncertain. Here, we performed single subject analyses in 22 patients in early stages of Huntington disease (HD), a neurodegenerative disorder with a well-known and characteristic pattern of GM loss. MATERIALS AND METHODS: We applied an ANCOVA with age and gender as covariates and corrected for multiple statistical tests by false discovery rate (P < 0.05). Each patient was compared to 133 healthy controls. The same procedure was applied to 22 of the controls matched for age and gender in a pair-wise manner. RESULTS: Our analyses yielded biologically plausible results in HD patients in which GM decrease within the caudate nucleus could be identified in 15 of the 16 most affected patients while GM decrease was found in only 1 control subject. Lowering the size of the control group yielded comparable results with 99 and 66 control subjects whereas sensitivity decreased with 33 control subjects. CONCLUSIONS: Our pilot study demonstrates a potential role of VBM for the detection of cerebral GM changes in single subjects with suspected neurodegenerative disorder.

[Contact heat evoked potentials for the evaluation of pain pathways]. / Kontakthitzeevozierte Potenziale. Diagnostische Option für die Evaluation des Schmerzsystems.

Pain evoked potentials offer a possibility for the evaluation of nociceptive pathways. Contact heat evoked potentials (CHEPS) represent a novel technique allowing to investigate peripheral pain pathways represented by small-diameter nerve fibers (A-delta and C fibers) and to study the spinothalamic tract. In contrast to more time-consuming methods such as quantitative sensory testing, CHEPS enables an objective investigation of pain pathways. This article reviews and discusses the technique, possible indications, and pitfalls in the context of clinical cases.

Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder.

Idiopathic chronic pain conditions with a mismatch between anatomical abnormalities and symptoms can be categorized as somatoform pain disorder according to the DSM-IV criteria. A dysfunction of pain processing circuits has been suggested as one underlying pathophysiological factor. There is accumulating evidence for a crucial role of affect regulating brain structures such as the medial frontal cortex in this context. We investigated the cerebral processing of noxious heat stimuli as objective marker for pain sensation in 12 right handed women with somatoform pain disorder fulfilling DSM-IV criteria and 13 age-matched healthy volunteers using functional MRI. The average ratings for experimentally induced pain were not significantly different between controls and patients concerning pain intensity and pain unpleasantness. Comparing patients with controls a pain related hypoactive state of the ventromedial prefrontal/orbitofrontal cortex (BA 10/11) and a hyperactive state of the parahippocampal gyrus, amygdala and anterior insula were found in the patient group. Our findings of an altered cerebral processing of experimentally induced pain in patients with somatoform pain disorder support the hypothesis of dysfunctional pain processing, especially in affect regulating regions.

Altered metabolism in frontal brain circuits in cluster headache.

Neuroimaging studies have explored cerebral activation patterns in patients with cluster headache (CH) during attacks and have revealed activation of multiple brain areas known to belong to the general pain-processing network. However, it is still unclear which changes in brain metabolism are inherent to the shift from the 'in bout' to the 'out of bout' period. We measured cerebral glucose metabolism in 11 episodic CH patients during the cluster and again during the remission period with (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) and compared these data with 11 healthy controls. 'In bout' compared with 'out of bout' scans were associated with increases of metabolism in the perigenual anterior cingulate cortex (ACC), posterior cingulate cortex, prefrontal cortex, insula, thalamus and temporal cortex. Decreases in metabolism were observed in the cerebellopontine area. Compared with healthy volunteers, hypometabolism in the patient group ('in bout' and 'out of bout') was found in the perigenual ACC, prefrontal and orbitofrontal cortex. Thus, FDG-PET in CH patients revealed 'in bout' activation of brain structures which are involved in descending pain control. Compared with controls, the regional brain metabolism was constitutively decreased in most of these structures, irrespective of the bout. This finding indicates a deficient top-down modulation of antinociceptive circuits in CH patients. We suggest that trigger mechanisms of CH are insufficiently controlled and thus promote the initiation of the bout period and acute attack.

[Pain and consciousness. Articles from the summer workshop held by the German Interdisciplinary Collaboration for Pain Therapy (DIVS) in 2005]. / Schmerz und Bewusstsein. Beiträge des Sommerworkshops der Deutschen Interdisziplinären Vereinigung für Schmerztherapie e.V. (DIVS) 2005.

Six articles are presented which illustrate the activities at the summer workshop "Pain and awareness" held 27-28 May 2005 in Marienfeld by the German Interdisciplinary Collaboration for Pain Therapy (DIVS). One article on pain constructs in the mind explains the advantages of functional imaging methods: these enable characterization of partial aspects of pain processing in the brain and the mechanisms that lead to chronic states of pain syndromes. A further overview explains the influence of different drugs on pain perception and various conscious states. How back pain patients experience their illness was analyzed in a study using an explanatory model interview: somatic aspects were dominant, but in three-fourths of the patients psychological illness attributions also played a role. A summary from the perspective of religious history and theology explores how pain is interpreted and accepted in various religious communities. Another article addresses hypnosis as a complementary technique to anesthesia procedures in surgical medicine, for treating chronic pain and experimental acute pain. The last contribution deals with how people in different cultures experience pain: ethnocentric bias can lead to difficulties in communication and misjudgments when treating foreign-born patients. All in all the workshop highlighted important formative factors in pain processing in a condensed form and offered stimulating perspectives for this area of pain research and future treatment options.

[Positron emission tomography in pain research. From the structure to the activity of the opiate receptor system]. / Positronenemissionstomographie (PET) in der Schmerzforschung. Von der Struktur zur Aktivität des Opiatrezeptorsystems.

Over the last decades, functional imaging studies have fostered our knowledge of cerebral pain processing in humans. A lively interest has been focussing on possible opioidergic mechanisms of pain transmission and modulation. Today, reliable knowledge of the in vivo distribution of opioid receptors in healthy human subjects is available from positron emission tomography (PET) studies of opioidergic neurotransmission. Gender dependent differences in receptor distribution and ligand metabolism have been demonstrated. Moreover, an increasing number of studies are reporting alterations in receptor distribution patterns in states involving painful diseases. Various acute painful challenges have also been shown to induce measurable changes in receptor availability in multiple brain areas. The perigenual anterior cingulate cortex (ACC) has been identified as one brain region with a major impact on opioidergic pain modulation. Thereby, the ACC apparently executes cortical top-down control on brainstem structures in (exogenous) pharmacological opioid analgesia. In addition, accumulating evidence suggests that non-pharmacological treatment approaches also utilize similar endogenous opioid dependent pathways to exert pain modulation. This article summarizes our current knowledge of PET studies of the opioidergic system and outlines future perspectives.

Voxel-based morphometry indicates relative preservation of the limbic prefrontal cortex in early Huntington disease.

In Huntington disease (HD), both the genetic defect and mutant gene product huntington are known but the exact mechanisms that lead to neuronal loss are poorly understood. Until now, the distribution of tissue loss throughout the brain has been investigated intensively. Here we searched for areas that, antipodal to the striatum, display grey-matter (GM) preservation. We performed high resolution T1-weighted magnetic resonance imaging and voxel-based morphometry in 46 patients in early HD and 46 healthy controls. We applied an analysis of covariance (ANCOVA) model with the total GM volume of each participant as covariate. In accordance with earlier reports, group comparisons revealed GM decrease in the striatum, insula, and thalamus as well as in dorsolateral frontal and occipital areas. In contrast, the limbic prefrontal cortex displayed GM preservation. Our findings support hypotheses that postulate differential involvement of frontosubcortical circuits in the pathophysiology of HD.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values.

The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Opioidergic changes in the pineal gland and hypothalamus in cluster headache: a ligand PET study.

Using PET with the opioidergic ligand [11C]diprenorphine, the authors demonstrate decreased tracer binding in the pineal gland of cluster headache patients vs healthy volunteers. Opioid receptor availability in the hypothalamus and cingulate cortex depended on the duration of the headache disorder. Therefore, the pathophysiology of cluster headache may relate to opioidergic dysfunction in circuitries generating the biologic clock.