Prefrontal but not cerebellar tDCS attenuates renewal of extinguished conditioned eyeblink responses.

An extended neural network is known to underlie extinction learning. As yet, comparatively little is known about the possible contribution of the cerebellum and the dorsolateral prefrontal cortex (dlPFC). In the present study, transcranial direct current stimulation (tDCS) was used to provide further evidence that the dlPFC and the cerebellum are involved in extinction-related processes. A total of 100 young and healthy human participants were randomly assigned to one of five stimulation groups: (1) anodal tDCS of the cerebellum, (2) cathodal tDCS of the cerebellum, (3) anodal tDCS of the dlPFC, (4) cathodal tDCS of the dlPFC, and (5) sham stimulation. Participants underwent delay eyeblink conditioning using an A-B-A/B renewal paradigm. Two different colors of background light (orange and blue) were used as contexts. On day 1, acquisition of conditioned eyeblink responses was performed in context A, followed by extinction in context B. tDCS was applied during extinction. On day 2, extinction recall was tested in contexts A and B with higher incidence of conditioned responses in acquisition context A compared to extinction context B indicating renewal effects. All groups showed significant effects of acquisition of conditioned eyeblink responses and significant effects of extinction. There was no significant difference in extinction between stimulation groups. During extinction recall, renewal effects were present in all groups, except the group which had received anodal tDCS of the dlPFC during extinction. In the present study, no direct effects of dlPFC or cerebellar tDCS were demonstrated on extinction. Anodal tDCS of the dlPFC, but not the cerebellum, resulted in delayed effects on context-related processes of extinction, possibly explained by shifting attention away from the context and towards the conditioned stimulus during extinction learning. Anodal tDCS of the dlPFC attenuated context-related recall of learned aversive responses. Effects of tDCS, however, were weak and need to be confirmed in future studies. Lack of cerebellar tDCS effects do not exclude a possible role of the cerebellum in extinction-related processes, and are likely explained by methodological limitations of cerebellar tDCS.

Altered Cerebellar Activity in Visceral Pain-Related Fear Conditioning in Irritable Bowel Syndrome.

There is evidence to support a role of the cerebellum in emotional learning processes, which are demonstrably altered in patients with chronic pain. We tested if cerebellar activation is altered during visceral pain-related fear conditioning and extinction in irritable bowel syndrome (IBS). Cerebellar blood oxygenation level-dependent (BOLD) data from N = 17 IBS patients and N = 21 healthy controls, collected as part of a previous fMRI study, was reanalyzed utilizing an advanced normalizing method of the cerebellum. The differential fear conditioning paradigm consisted of acquisition, extinction, and reinstatement phases. During acquisition, two visual conditioned stimuli (CS) were presented either paired (CS+) or unpaired (CS-) with painful rectal distension as unconditioned stimulus (US). In the extinction phase, the CS+ and CS- were presented without US. For reinstatement, unpaired US presentations were followed by unpaired CS+ and CS- presentations. Group differences in cerebellar activation were analyzed for the contrasts CS+ > CS- and CS- > CS+. During acquisition, IBS patients revealed significantly enhanced cerebellar BOLD responses to pain-predictive (CS+) and safety (CS-) cues compared to controls (p < 0.05, family-wise error corrected). Increased activation was found in three main clusters, including the vermis (maximum in vermal lobule VI), intermediate cerebellum (maximum in lobule VIII), and the posterolateral cerebellar hemisphere (maximum in lobule VI). Areas overlapped for the contrasts CS+ > CS- and CS- > CS+. Group differences were most prominent in the contrast CS- > CS+. During extinction and reinstatement, no significant group differences were found. During visceral pain-related fear conditioning, IBS patients showed increased activations in circumscribed areas of the medial, intermediate, and lateral cerebellum. These areas are involved in autonomic, somatosensory, and cognitive functions and likely contribute to the different aspects of pain-related fear. The cerebellum contributes to altered pain-related fear learning in IBS.

Cerebellar Contribution to Context Processing in Extinction Learning and Recall.

Whereas acquisition of new associations is considered largely independent of the context, context dependency is a hallmark of extinction of the learned associations. The hippocampus and the prefrontal cortex are known to be involved in context processing during extinction learning and recall. Although the cerebellum has known functional and anatomic connections to the hippocampus and the prefrontal cortex, cerebellar contributions to context processing of extinction have rarely been studied. In the present study, we reanalyzed functional brain imaging data (fMRI) of previous work investigating context effects during extinction in a cognitive associative learning paradigm in 28 young and healthy subjects (Lissek et al. Neuroimage. 81:131-3, 2013). In that study, event-related fMRI analysis did not include the cerebellum. The 3 T fMRI dataset was reanalyzed using a spatial normalization method optimized for the cerebellum. Data of seven participants had to be excluded because the cerebellum had not been scanned in full. Cerebellar activation related to context change during extinction learning was most prominent in lobule Crus II bilaterally (p < 0.01, t > 2.53; partially corrected by predetermined cluster size). No significant cerebellar activations were observed related to context change during extinction retrieval. The posterolateral cerebellum appears to contribute to context-related processes during extinction learning, but not (or less) during extinction retrieval. The cerebellum may support context learning during extinction via its connections to the hippocampus. Alternatively, the cerebellum may support the shifting of attention to the context via its known connections to the dorsolateral prefrontal cortex. Because the ventromedial prefrontal cortex (vmPFC) is critically involved in context-related processes during extinction retrieval, and there are no known connections between the cerebellum and the vmPFC, the cerebellum may be less important during extinction recall.

Pronounced reduction of acquisition of conditioned eyeblink responses in young adults with focal cerebellar lesions impedes conclusions on the role of the cerebellum in extinction and savings.

Human cerebellar lesion studies provide good evidence that the cerebellum contributes to the acquisition of classically conditioned eyeblink responses (CRs). As yet, only one study used more advanced methods of lesion-symptom (or lesion-behavior) mapping to investigate which cerebellar areas are involved in CR acquisition in humans. Likewise, comparatively few studies investigated the contribution of the human cerebellum to CR extinction and savings. In this present study, young adults with focal cerebellar disease were tested. A subset of participants was expected to acquire enough conditioned responses to allow the investigation of extinction and saving effects. 19 participants with chronic surgical lesions of the cerebellum and 19 matched control subjects were tested. In all cerebellar subjects benign tumors of the cerebellum had been surgically removed. Eyeblink conditioning was performed using a standard short delay protocol. An initial unpaired control phase was followed by an acquisition phase, an extinction phase and a subsequent reacquisition phase. Structural 3T magnetic resonance images of the brain were acquired on the day of testing. Cerebellar lesions were normalized using methods optimized for the cerebellum. Subtraction analysis and Liebermeister tests were used to perform lesion-symptom mapping. As expected, CR acquisition was significantly reduced in cerebellar subjects compared to controls. Reduced CR acquisition was significantly more likely in participants with lesions of lobule VI and Crus I extending into Crus II (p<0.05, Liebermeister test). Cerebellar subjects could be subdivided into two groups: a smaller group (n=5) which showed acquisition, extinction and savings within the normal range; and a larger group (n=14) which did not show acquisition. In the latter, no conclusions on extinction or savings could be drawn. Previous findings were confirmed that circumscribed areas in lobule VI and Crus I are of major importance in CR acquisition. In addition, the present data suggest that if the critical regions of the cerebellar cortex are lesioned, the ability to acquire CRs is not only reduced but abolished. Subjects with lesions outside these critical areas, on the other hand show preserved acquisition, extinction and saving effects. As a consequence, studies in human subjects with cerebellar lesions do not allow drawing conclusions on CR extinction and savings. In light of the present findings, previous reports of reduced extinction in humans with circumscribed cerebellar disease need to be critically reevaluated.

Cerebellar vermis contributes to the extinction of conditioned fear.

The cerebellum is known to contribute to the acquisition and retention of conditioned motor and emotional responses. Eyeblink conditioning and fear conditioning have been studied in greatest detail. Whereas a considerable number of studies have shown that the cerebellum is also involved in extinction of conditioned eyeblink responses, the likely contribution of the cerebellum to extinction of conditioned fear responses has largely been ignored. In the present study, we analyzed functional brain imaging data (fMRI) of previous work investigating extinction of conditioned fear in 32 young and healthy men, in which event-related fMRI analysis did not include the cerebellum. This dataset was analyzed using a spatial normalization method optimized for the cerebellum. During fear acquisition, an unpleasant electric shock (unconditioned stimulus; US) was paired with one of two pictures of geometrical figures (conditioned stimulus; CS+), while the other picture (CS-) was never paired with the US. During extinction, CS+ and CS- were presented without the US. During the acquisition phase, the fMRI signal related to the CS+ was significantly higher in hemispheric lobule VI in early compared to late acquisition (p<.05, permutation corrected). During the extinction phase, the fMRI signal related to the contrast CS+>CS- was significantly higher within the anterior vermis in early compared to late extinction (p<.05, permutation corrected). The present data show that the cerebellum is not only associated with the acquisition but also with the extinction of conditioned fear.

Studies of cellular mediated immunity in malignant melanoma patients by Leukocyte Adherence Inhibition Test.

Sixteen malignant melanoma patients with different levels of tumor progression, two patients with melanoma in situ (Clark 10 two bronchogenic carcinoma patients and nine healthy controls were tested by means of the leukocyte adherence inhibition (LAI) test to assess the function of their cellular mediated immunity. Blood leukocytes were incubated with allogeneic melanoma-associated antigen obtained from potassium chloride extract of tumor cells. Fifteen malignant melanoma patients with clinical stage I-III (Clark level 2-5) showed positive LAI-reaction when leukocytes were tested with melanoma associated antigen. Leukocyte adherence inhibition was neither monitored in healthy controls, in patients with melanoma in situ, nor in those two patients with squamous and oat cell type bronchogenic carcinoma. Extracts prepared from normal skin showed no inhibitive effect on leukocyte adherence in malignant melanoma patients and controls. A decreased percentage of LAI was observed in malignant melanoma patients with disseminated disease due to an increased spontaneous leukocyte adherence in these patients. This increase in spontaneous leukocyte adherence was probably caused by non-specific activation of adherent cells (macrophages) as a result of the prolonged therapy and/or the progressive tumor levels in these patients.

Localized in vivo 1H magnetic resonance spectroscopy and in vitro analyses of heterogeneous brain tumors.

Results of magnetic resonance spectroscopic (MRS) studies of the chemical patterns in brain tumors have been inconsistent. Actual biochemical correlations are needed. In 2 patients with heterogeneous intracranial tumors, in vivo 1H MRS and in vitro biochemical analyses were correlated. Histology confirmed the tumor heterogeneity. Choline was elevated in the cellular portion of both tumors but decreased in the necrotic or cystic portions. Creatine was diffusely decreased while lactate was elevated in all regions of both tumors. Furthermore, the increase in the choline peak on 1H MRS appeared to be due to increases in water-soluble choline compounds. This study illustrates the value of small localized voxels for differentiating regional chemical differences in tumors.

[Reaction of autogenous cortisol production in patients with extensive psoriasis vulgaris or atopic dermatitis following external administration of a 0.25% prednicarbate salve (W/O emulsion)]. / Reaktion der körpereigenen Cortisol-Produktion bei Patienten mit ausgedehnter Psoriasis vulgaris oder atopischer Dermatitis nach externer Applikation einer 0.25%igen Prednicarbat-Salbe (W/O-Emulsion).

Prednicarbate is a new potent corticoid without halogenic groups which has been developed for topical application. During one week's application of 0.25% prednicarbate ointment (W/O Emulsion) two times daily in an ordinary dose, there could not be proved any significant suppression of the basal production of plasma cortisol in patients suffering from extensive dermatoses (such as psoriasis vulgaris or atopic dermatitis). After the end of treatment, investigation on the reservoir within the adrenal cortex by means of ACTH short test showed sufficient stimulation capacity of the adrenal gland in all patients examined.

[Dithranol-urea treatment of chronic psoriasis. A comparison of 0,1% dithranol + 17% urea with triamcinolone acetonite 0,1% and phototherapy (author's transl)]. / Dithranol-Harnstofftherapie bei Psoriasis vulgaris. Vergleichende Untersuchungen von Dithranol 0,1% + Harnstoff 17% mit Triamcinolonacetonid 0,1% und Phototherapie.

The topical treatment of active chronic psoriasis can be achieved as effectively with 0,1% dithranol + 17% urea as with triamcinolone acetonite 0,1%. Compared with salicylic acid + dithranol preparations, the latter when combined with urea show a delayed clinical response, but less side effects. UVB in combination with the dithranol/urea preparation seems to be more efficient, without an increment of adverse effects. It would appear than an addition of urea offers an acceptable and effective alternative to salicylic acid.

[Macrophotographic correlates of the histology of precursor nevi and SSM in relation to the McGovern model]. / Makrophotographische Korrelate zur Histologie bei Precursor-Naevi und SSM in Anlehnung an das Schema von McGovern.

Structures within pigmented skin tumors, which are beyond the dissolving powers of the eye, may be analysed in vivo by macroscopy using incident lighting. Benign melanocytic nevi have a symmetric and distinct horizontal pattern of pigmentation, whereas in melanoma, intraepidermal tumor growth may show coexistence of net- and/or cluster-like and non-structural forms of pigmentation.

[Immunophenotyping and morphometry of inflammatory infiltrates in variants of basalioma]. / Immunphänotypisierung und Morphometrie des entzündlichen Infiltrates bei Basaliomvarianten.

The inflammatory infiltrate of 5 histologically different types of basal cell carcinoma (BCC) (n = 22) was characterized by means of the alkaline phosphatase monoclonal antialkaline phosphatase technique (APAAP). We proved a distinct stromal pattern of infiltration, which was focally accentuated; in some cases, the cells infiltrated the tumor itself. On phenotyping these cells, we found clear predominance of T cells (75%), which mostly consisted of T helper/inducer cells (45%) and suppressor/cytotoxic cells (32%); in addition, we found B cells (6%) as well as monocytes and macrophages (15%). Morphea-like and adenoid types of BCC showed some tendency to a less pronounced infiltration. Chronic exposure to sunlight and ulceration did not significantly influence the quality or quantity of the inflammatory infiltrate--except for polymorphonuclear leucocytes and macrophages.

[Develop of localized pemphigoid following radiation treatment (author's transl)]. / Induktion eines lokalisierten Pemphigoids durch energiereiche Strahlen.

A case of localized bullous pemphigoid in a 79-year-old woman is reported. The symptoms developed 5 months following radiation treatment of breast cancer. Direct immunofluorescence investigations showed IgG and C3 deposition in the basement membrane zone (BMZ) of lesional skin. Serum BMZ antibodies (IgG, IgM) and C3 deposition were demonstrated. Light microscopic investigation revealed subepidermal blister formation. A cellular infiltrate consisted predominantly of lymphocytes and eosinophils in the upper dermis. Junctional blister formation, located within the lamina lucida of the basement membrane, was confirmed by electron microscopy. Differential diagnoses and various possible etiologies are discussed.

[Crosti's dorsal reticulosis--a histiocytic lymphoma of a low degree of malignancy]. / Reticulosis dorsi Crosti--ein histiocytäres Lymphom geringen Malignitätsgrades.

We report on the clinical and histological course of a lymphoma-like process similar to Crosti's dorsal reticulosis. Histological findings revealed a non-epidermotropic mixed cellular infiltration of histiocytes und T-lymphocytes with high and spontaneous cell destruction. We also observed high radiosensitivity.

Transcription of episomal papillomavirus DNA in human condylomata acuminata and Buschke-Löwenstein tumours.

Condylomata acuminata and Buschke-Löwenstein tumours were analysed for the presence of human papillomavirus (HPV) transcripts. HPV DNA and RNA sequences were present in all 13 samples investigated. Ten contained HPV6 and three harboured HPV11. The HPV genomes were found exclusively as extrachromosomal circular molecules. In six biopsy specimens, viral RNA transcripts were not detectable by Northern blot analysis but could be demonstrated in dot blots. From seven HPV6-containing samples it was possible to obtain sufficient amounts of undegraded mRNA. We have found consistently one major species (1.4 kb). Less prominent species of 1.7, 1.85, 2.7 and 3.2 kb, respectively, were also detected. The 3' ends of the HPV6 mRNAs were located between nucleotides 3917 and 4441 in the putative early region and between nucleotides 7232 and 7696 in the putative late region. The arrangement of the 3' termini and the adjacent coding areas within the HPV6 genome show that the RNA species are transcribed from one DNA strand.

Influence of dextran polymer particles (Sephadex G-200) on humoral immune responses.

Dextran polymer particles (Sephadex G-200) mixed with bovine serum albumin (BSA) or sheep red blood cells (SRBC) were injected intraperitoneally (i.p.) into mice and the number of antibody-forming cells in spleen and antibody titers in sera were determined. Antibody formation following the first and the booster immunization to BSA was enhanced to a similar degree by Sephadex G-200 and incomplete Freund's adjuvant. When SRBC were injected in a suboptimal dose of 5X10(6) cells, Sephadex G-200 enhanced the maximum of the primary immune response. In contrast, the polymer inhibited the primary and secondary immune response when 5X10(8) SRBC were given.

[Macrophotography in transmitted light. Contribution to an analysis of horizontal structures of pigmented skin tumors]. / Makrofotografie im transmittierten Licht. Ein Beitrag zur horizontalen Strukturanalyse pigmentierter Hauttumoren.

Macrophotography leads to better comprehension of the horizontal plane of pigmented skin lesions. It issues supplementary data for early clinical diagnosis and differentiation of malignant skin tumors. Strong contrast and increased depth of field in transmitted light can give additional data.

[Multiple generalized glomus tumors. Morphologic and biochemical findings]. / Multiple generalisierte Glomustumoren. Morphologische und biochemische Befunde.

A 54 year-old woman developed approximately 150 generalized glomus tumors since she had been 23 years old. Painful tumors showed more glomus cells than those being not painful. Furthermore, the patient suffered from persisting congenital capillary hemangioma (strawberry mark). Histological examination revealed that glomus cells were located in the vessel walls. The large amount of Dopa found in the glomus tumor tissue supports the assumption that it may be innervated by adrenergic efferent nerves.

Cerebral toxoplasmosis and lymphoma in AIDS: perfusion MR imaging experience in 13 patients.

PURPOSE: To evaluate the perfusion magnetic resonance (MR) imaging characteristics of cerebral toxoplasmosis and lymphoma in patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Perfusion MR imaging was performed prospectively in 13 patients with AIDS who had contrast material-enhancing focal brain lesions (six with active lymphoma, five with toxoplasmosis, one with treated lymphoma in remission, and one with toxoplasmosis plus lymphomatoid granulomatosis). Regional cerebral blood volume (rCBV) was determined by using dynamic echo-planar MR imaging during bolus injection of a gadolinium chelate. RESULTS: The rCBV was decreased (44% +/- 24 [standard deviation] of rCBV in the contralateral regions) throughout the toxoplasmosis lesions and in the surrounding edema of both lesion types, whereas all active lymphomas displayed areas of increased rCBV (258% +/- 99). These differences were significant (P < .005). CONCLUSION: Reduced rCBV i toxoplasmosis lesions is probably due to a lack of vasculature within the abscess; increased rCBV in lymphomas is probably due to hypervascularity in foci of active tumor growth; and decreased rCBV in the edema is probably due to vasoconstriction associated with increased interstitial pressure. Perfusion MR imaging is a rapid, noninvasive tool that may allow differentiation between cerebral lymphoma and toxoplasmosis in patients with AIDS.

Once daily mometasone furoate aqueous nasal spray is as effective as twice daily beclomethasone dipropionate for treating perennial allergic rhinitis patients.

BACKGROUND: Perennial allergic rhinitis is chronic and persistent, may lead to a constellation of secondary complaints including sinusitis, mouth-breathing, and some symptoms resembling a permanent cold, and often requires constant medical intervention. Well-tolerated nasal corticosteroids, alone or in combination with antihistamines, have been found to be very effective in treating this condition. OBJECTIVE: To compare the effectiveness and tolerability of mometasone furoate aqueous suspension, a new once daily nasal spray, to placebo vehicle and to beclomethasone dipropionate, administered twice daily, in patients with perennial allergic rhinitis. METHODS: This was a randomized, double-blind, placebo-controlled, double-dummy, parallel group study, in 427 patients age 12 years and older at 24 centers in Canada and Europe. Patients allergic to at least one perennial allergen, confirmed by medical history, skin testing, and adequate symptomatology were eligible to receive one of the following regimens for 3 months: mometasone furoate, 200 micrograms only daily; beclomethasone dipropionate, 200 micrograms twice daily (400 micrograms total dose); or placebo vehicle control. The primary efficacy variable was the change from baseline in total AM plus PM diary nasal symptom score over the first 15 days of treatment. RESULTS: Three hundred eighty-seven patients were valid for efficacy. For the primary efficacy variable, mometasone furoate was significantly (P < or = .01) more effective than placebo and was indistinguishable from beclomethasone dipropionate. Similar trends were seen among individual symptoms, physician symptom evaluations, and therapeutic response. There was no evidence of tachyphylaxis. All treatments were well tolerated. CONCLUSIONS: Mometasone furoate nasal spray adequately controls symptoms of perennial allergic rhinitis, offers the advantage of once daily treatment, and is well tolerated.