Howard C. Tenenbaum

Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination.

Rumination is a form of thought characterized by repetitive focus on discomforting emotions or stimuli. In chronic pain disorders, rumination can impede treatment efficacy. The brain mechanisms underlying rumination about chronic pain are not understood. Interestingly, a link between rumination and functional connectivity (FC) of the brains default mode network (DMN) has been identified within the context of mood disorders. We, and others, have also found DMN dysfunction in chronic pain populations. The medial prefrontal cortex (mPFC) is a key node of the DMN that is anatomically connected with the descending pain modulatory system. Therefore, we tested the hypothesis that in patients with chronic pain, the mPFC exhibits abnormal FC related to the patients degree of rumination about their pain. Seventeen patients with idiopathic temporomandibular disorder (TMD) and 17 age- and sex-matched healthy controls underwent resting state functional MRI, and rumination about pain was assessed through the rumination subscale of the Pain Catastrophizing Scale. Compared with healthy controls, we found that TMD patients exhibited enhanced mPFC FC with other DMN regions, including the posterior cingulate cortex (PCC)/precuneus (PCu) and retrosplenial cortex. We also found that individual differences in pain rumination in the chronic pain patients (but not in healthy controls) were positively correlated to mPFC FC with the PCC/PCu, retrosplenial cortex, medial thalamus, and periaqueductal/periventricular gray. These data implicate communication within the DMN and of the DMN with the descending modulatory system as a mechanism underlying the degree to which patients ruminate about their chronic pain.

Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder.

Cortical plasticity is thought to occur following continuous barrage of nociceptive afferent signals to the brain. Hence, chronic pain is presumed to induce anatomical and physiological changes in the brain over time. Inherent factors, some pre-dating the onset of chronic pain, may also contribute to brain abnormalities present in patients. In this study we used structural MRI to examine whether patients with chronic temporomandibular (TMD) pain have abnormalities in gray matter (GM) within brain areas implicated in pain, modulation and sensorimotor function. We found that patients with TMD have cortical thickening in the primary somatosensory cortex (S1), frontal polar and the ventrolateral prefrontal cortex (PFC). These findings provide a structural basis for previous findings of TMD pain and cognitive sluggishness in TMD. We then examined the contribution of TMD characteristics to GM abnormalities. We found that 1) GM in the sensory thalamus positively correlated to TMD duration, 2) cortical thickness in the primary motor (M1) and the anterior mid-cingulate cortices (aMCC) were negatively correlated to pain intensity, and 3) pain unpleasantness was negatively correlated to cortical thickness in the orbitofrontal cortex (OFC). These findings suggest that an individuals TMD pain history contributes to GM in the brain. Lastly, we examined the contribution of a potential pre-existing vulnerability due to neuroticism. In the TMD patients, we found that there was an abnormal positive correlation between neuroticism and OFC thickness, in contrast to the negative correlation found in the healthy controls. Therefore, neuroticism may contribute to TMD pathophysiology. In sum, our data suggest that GM in the brain of patients with chronic TMD pain can be shaped by both personality and pain characteristics.

The Effect of Photodynamic Therapy for Periodontitis: A Systematic Review and Meta-Analysis

BACKGROUND The purpose of this review was to evaluate the effectiveness of photodynamic therapy (PDT) for periodontitis in adults as a primary mode of treatment or as an adjunct to non-surgical treatment of scaling and root planing (SRP) compared to a conventional non-surgical SRP treatment. METHODS MEDLINE, EMBASE, CINAHL, other relevant databases, and the International Pharmaceutical Abstracts were searched from their inception until May 2009 for randomized controlled trials of PDT compared to a placebo, no intervention, or non-surgical treatment in an adult population. Data on changes in clinical attachment level (CAL), probing depth, gingival recession, and full-mouth plaque or bleeding scores were extracted and meta-analyzed, and the pooled mean difference (MD) was reported. RESULTS Five studies were included in this review. These studies had a small sample size for some of the performed analysis with a moderate to high risk of biases. There were clinical heterogeneities among included studies. PDT as an independent treatment or as an adjunct to SRP versus a control group of SRP did not demonstrate statistically or clinically significant advantages. Combined therapy of PDT + SRP indicated a probable efficacy in CAL gain (MD: 0.34; 95% confidence interval [CI]: 0.05 to 0.63) or probing depth reduction (MD: 0.25 mm; 95% CI: 0.04 to 0.45 mm). CONCLUSIONS PDT as an independent treatment or as an adjunct to SRP was not superior to control treatment of SRP. Therefore, the routine use of PDT for clinical management of periodontitis cannot be recommended. Well-designed clinical trials are needed for proper evaluation of this therapy.

White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.

Summary Temporomandibular disorder patients have white matter abnormalities along the trigeminal nerve and pain‐related brain pathways, and abnormal connectivity of cognitive‐affective brain regions. ABSTRACT Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly understood. Recent imaging studies reported functional and gray matter abnormalities in brain areas implicated in sensorimotor, modulatory, and cognitive function in TMD, but it is not known whether there are white matter (WM) abnormalities along the trigeminal nerve (CNV) or in the brain. Here, we used diffusion tensor imaging, and found that, compared to healthy controls, TMD patients had 1) lower fractional anisotropy (FA) in both CNVs; 2) a negative correlation between FA of the right CNV and pain duration; and 3) diffuse abnormalities in the microstructure of WM tracts related to sensory, motor, cognitive, and pain functions, with a highly significant focal abnormality in the corpus callosum. Using probabilistic tractography, we found that the corpus callosum in patients had a higher connection probability to the frontal pole, and a lower connection probability to the dorsolateral prefrontal cortex, compared to controls. Finally, we found that 1) FA in tracts adjacent to the ventrolateral prefrontal cortex and tracts coursing through the thalamus negatively correlated with pain intensity; 2) FA in the internal capsule negatively correlated with pain intensity and unpleasantness; and 3) decreases in brain FA were associated with increases in mean diffusivity and radial diffusivity, markers of inflammation and oedema. These data provide novel evidence for CNV microstructural abnormalities that may be caused by increased nociceptive activity, accompanied by abnormalities along central WM pathways in TMD.

Diabetes and Periodontal Diseases: Interplay and Links

The association between diabetes and periodontal diseases is well-established. Diabetes is a risk factor for periodontal disease, with diabetic patients exhibiting an increased prevalence, extent and severity of gingivitis and perio- dontitis compared to healthy adults. Several mechanisms involved in the pathogenesis of diabetes have also been associated with periodontal disease progression. It is recognized today that there is a bidirectional relationship between diabetes and periodontal disease, with recent research showing that periodontal disease may affect the metabolic control of diabetes in diabetic patients. In this review, we present the current knowledge of the interplay between periodontal diseases and diabetes through the evaluation of randomized control and longitudinal cohort studies published in the past 15 years. Current data support the conclusion that diabetic patients are at increased risk for periodontal diseases, and that patients with poorly controlled diabetes are at risk for severe periodontitis. This results in the destruction of oral connective tissue and generalized bone loss, leading ultimately to tooth loss. Although the effect of periodontal disease on glycemic control in type 1 diabetic patients is controversial, evidence does show a direct correlation between periodontal health and glycemic control in type 2 diabetic patients. Furthermore, several studies have demonstrated the beneficial effect of periodontal treatment on metabolic control of type 2 diabetic patients.

Expression of bone sialoprotein and osteopontin in breast cancer bone metastases

Bone sialoprotein (BSP) and osteopontin (OPN) are prominent, mineral-associated proteins in the extracellular matrix of bone that have been implicated in the metastatic activity of cancer cells. The expression of BSP, which is normally restricted to mineralizing tissues, has been observed in cancers with a high propensity for forming bone metastases. To investigate the relationship between BSP expression and the formation of bone metastases we have conducted an initial study of the expression of BSP in 10 intraductal breast carcinoma bone metastases using immunostaining and in situ hybridization, and compared the expression with OPN. The metastases were characterized by the infiltration of tumour cells into bone with extensive bone resorption evident. Moderate to strong staining for BSP was observed in all (100%) carcinomas, which also expressed BSP mRNA as determined by in situ hybridization. Variable staining for BSP was also observed in the mineralized bone and expression of BSP mRNA could be observed in osteoblastic cells on the bone surface and in some osteocytes at sites of bone remodelling. Contrary to a previous report, BSP expression could be demonstrated by PCR in three breast cancer cell lines, MCF-7, T47-D and MDA-MB-231. Moreover, in sub-cutaneous tumours formed by MDA-MB-231 breast cancer cells injected into athymic mice, higher immunostaining for BSP was seen in large ulcerating tumours in which mineral deposits were formed. In contrast to BSP, staining for OPN in bone metastases was generally restricted to the interface between tumor cells and bone surface of the carcinomas. While OPN staining was also observed in the cytoplasm of osteoclasts, which showed strong hybridization to a digoxygenin-labelled OPN cRNA probe, expression of OPN was not clearly detectable in the tumour cells. These studies provide the first demonstration of BSP expression by tumour cells in bone metastases and support the concept that BSP may have a role in targeting metastatic cells to bone. Expression of OPN in bone metastases appears to be related to increased bone resorptive activity by osteoclasts.

Transplantation of labeled periodontal ligament cells promotes regeneration of alveolar bone.

Regeneration of damaged periodontal tissues is mediated by periodontal cells, but a major sub‐population comprises highly differentiated cells that do not renew. To overcome the loss of specialized cell types caused by disease, various therapeutic approaches including cell transplants have been developed to promote cell re‐population in periodontal tissues. As previous transplantation studies used unlabeled cells, that are indistinguishable from host cells, it has been difficult to assess the contributions of transplanted cells to the healing processes. To track the fate and differentiation of rat periodontal cells transplanted into periodontal wounds, we used collagen‐coated fluorescent beads as a permanent endocytosed marker, or cells constitutively expressing β‐galactosidase. We assessed osteogenic cell differentiation with immunohistochemical staining for osteopontin and bone sialoprotein. Cells were transplanted into periodontal wounds created in Sprague–Dawley male rats that are null for β‐galactosidase. Defects were allowed to heal spontaneously (controls), or were closed with collagen implants mixed with β‐galactosidase‐positive (Lac‐Z) periodontal cells, or closed with collagen implants mixed with periodontal cells loaded with fluorescent beads. Animals were killed at 1 and 2 weeks after surgery and tissues were prepared for morphometric assessment and immunostaining for osteopontin (OPN) and bone sialoprotein (BSP). Transplanted cells were easily distinguished by fluorescent beads or by β‐galactosidase‐positive expression and were distributed throughout the regenerating periodontal ligament (PL) and alveolar bone. At 1 week after wounding, animals treated with β‐galactosidase‐positive cells exhibited a slightly higher percentage of labeled cells in the PL compared with the fluorescent bead‐labeled cell implant group (2% vs. 1% respectively; P > 0.2). At Week 2 percentages of labeled cells were slightly increased in the regenerating PL (≈3% for both groups, P > 0.2). In regenerating alveolar bone at 1 week, animals that were treated with β‐galactosidase‐positive cells and fluorescent bead‐loaded cells exhibited ≈30% and 25% of labeled cells respectively. At 2 weeks after wounding there was an increase in the percentage of transplanted β‐galactosidase‐positive cells (≈ 39% at week 2; P < 0.05), but not of transplanted cells with fluorescent beads (≈25% at week 2). In sites with transplanted cells there were higher percentages of OPN positive and BSP positive cells in nascent bone and more newly formed bone than in controls (>40%; P < 0.05). Transplantation of β‐galactosidase‐positive cells or cells loaded with fluorescent beads is a useful method for assessing the fate and differentiation of periodontal cells in vivo. Fluorescent beads, however, are diluted at mitosis and this method underestimates the percentage of transplanted cells. As transplanted periodontal cells in both groups promoted regeneration of alveolar bone, cell transplantation could improve the restoration of periodontium destroyed by periodontitis. Anat Rec 262:193–202, 2001.

Is keratinized mucosa indispensable to maintain peri‐implant health? A systematic review of the literature

The significance of keratinized mucosa (KM) around dental implants is still not well explained and has been controversial. The aim of this systematic review was to evaluate the importance of KM around dental implants. The electronic databases Cochrane library, MEDLINE, EMBASE, and Virtual Health Library (VHL) databases were utilized to search original articles from 2006 to March 2013. The inclusion and exclusion criteria used to select the articles were: (1) Human studies published in the English language; (2) Study published in international peer-viewed journals; (3) Studies evaluated the association between KM width and the peri-implant tissue health; (4) Studies that have follow up of greater than 12 months; (5) Publication of studies not older than 10 years. The searches retrieved 285 citations. Seven articles fulfilled all of the inclusion criteria. Out of these, three studies were ranked as presenting high methodological quality, and four were judged to be of moderate quality. This systematic review concludes that the presence of an adequate zone of keratinized tissue may be necessary because it was shown to be related to better peri-implant tissue health. Further randomized controlled trials are necessary to support this statement.

NEW FACE OF AN OLD ENZYME : ALKALINE PHOSPHATASE MAY CONTRIBUTE TO HUMAN TISSUE AGING BY INDUCING TISSUE HARDENING AND CALCIFICATION

Tissue nonspecific alkaline phosphatase (AP) plays a well‐known role in bone mineralization. This role was first suggested by a human AP deficiency disease, hypophosphatasia. Further studies with AP gene knockout mice have also suggested a role for AP in mineralization. However, AP is also expressed in other human tissues besides bone and cartilage, and this raises a question as to whether AP may also play a role in pathological mineralization such as dystrophic and vascular calcification. In vitro studies carried out in our laboratory indicate that a variety of cell types stably expressing membrane‐bound AP can affect extracellular mineralization regardless of the tissue from which the cell lines originated (e.g. fibroblasts, vascular endothelial cells, or renal epithelial cells). This AP‐mediated extracellular mineralization is both substrate/dependent and culture environment/dependent and may be consistent with a putative role for AP in pathological mineralization in tissues other than bone and cartilage. In this regard, it is interesting to note that high levels of AP are observed in vascular endothelia of small arterioles in brain and heart. It is probable that expression of AP in small arterioles of brain and heart may also contribute to the vascular hardening and calcification observed in humans. This in turn could be related to vascular aging, vascular disease, and the resultant weakening of and/or rupture of vessel walls. Anat Rec. (New Anat.): 253:91–94, 1998.

Abnormal gray matter aging in chronic pain patients

Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent studies indicate that age-related GM changes are not uniform across the brain and may vary according to health status. Therefore the aims of this study were to determine whether chronic pain in temporomandibular disorder (TMD) is associated with abnormal GM aging in focal cortical regions associated with nociceptive processes, and the degree to which the cumulative effects of pain contributes to age effects. We found that patients have accelerated whole brain GM atrophy, compared to pain-free controls. We also identified three aberrant patterns of GM aging in five focal brain regions: 1) in the thalamus, GM volume correlated with age in the TMD patients but not in the control group; 2) in the anterior mid- and pregenual cingulate cortex (aMCC/pgACC), the TMD patients showed age-related cortical thinning, whereas the controls had age-related cortical thickening; and 3) in the dorsal striatum and the premotor cortex (PMC). Interestingly, the controls but not the patients showed age-related GM reductions. Finally, a result of particular note is that after accounting for the effects of TMD duration, age remained as a significant predictor of GM in the PMC and dorsal striatum. Thus, abnormal GM aging in TMD may be due to the progressive impact of TMD-related factors in pain-related regions, as well as inherent factors in motor regions, in patients with TMD. This study is the first to show that chronic pain is associated with abnormal GM aging in focal cortical regions associated with pain and motor processes.