Shariq A. Khan

Streptococcus mutans, Candida albicans, and the human mouth: a sticky situation

The human mouth with its diverse niches and ample supply of nutrients is undoubtedly conducive for the unrestricted formation of natural microbial biofilms. The oral microbial communities are some of the most complex microbial floras in the human body, consisting of more than 700 different bacterial species [1], [2]. Occurrence of disease results from disturbance of the equilibrium of this complex ecosystem, where population shifts lead to overrepresentation of pathogenic species which contribute to the onset and progression of the most common oral diseases, caries and periodontal disease [3]. Culture-independent molecular methods such as proteomics and 16S rRNA sequencing aiming to determine the bacterial diversity in the human oral cavity have demonstrated that in the supragingival plaque, S. mutans was the dominant species, with elevated levels of other streptococci including S. sanguinis, S. mitis, and S. salivarius in addition to lactobacilli and Veillonella. In contrast, the subgingival plaque was made up primarily of Gram-negative anaerobic bacteria such as Fusobacterium nucleatum, Porphyromonas gingivalis, and Prevotella intermedia which are known to be periodontal pathogens [3]–[5]. The dental tissues—enamel, dentin, and cementum—constitute the oral solid surfaces coated by a pellicle to which the microbial cells attach. The primary colonizers and secondary organisms stick to each other on the surface of teeth and generate a matrix of exopolysaccharide within which cells grow, forming a community with a collective physiology [6]. The resulting biofilm formed, known as dental plaque, subjects the teeth and gingival tissues to high concentrations of microbial metabolites which result in dental disease [2], [7]. The interactions between the various species in these mixed biofilms can be synergistic in that the presence of one microorganism generates a niche for other pathogenic microorganisms which can serve to facilitate the retention of organisms, an oral phenomenon known as coaggregation [3], [8]. The bacteria in the biofilm are always metabolically active which causes fluctuations in pH and loss of minerals from the tooth, ultimately resulting in dissolution of the dental hard tissues and formation of lesions known as dental caries [6], [9]. Interestingly, metabolic communications among oral bacteria may occur where the excretion of a metabolite by one organism is used as a nutrient by other organisms and breakdown of a substrate by enzymatic activity of one organism creates available substrates for different organisms [10], [11].

Altered structure and function in the hippocampus and medial prefrontal cortex in patients with burning mouth syndrome

Summary Patients with burning mouth syndrome had altered structure and function of the medial prefrontal cortex and hippocampus, which was partially explained by ongoing pain and depression scores. ABSTRACT Burning mouth syndrome (BMS) is a debilitating, idiopathic chronic pain condition. For many BMS patients, burning oral pain begins in late morning and becomes more intense throughout the day, peaking by late afternoon or evening. We investigated brain gray matter volume (GMV) with voxel‐based morphometry (VBM), white matter fractional anisotropy (FA) with diffusion tensor imaging (DTI), and functional connectivity in resting state functional MRI (rsfMRI) in a tightly screened, homogeneous sample of 9 female, postmenopausal/perimenopausal BMS patients and 9 matched healthy control subjects. Patients underwent 2 scanning sessions in the same day: in the morning, when ongoing pain/burning was low, and in the afternoon, when pain/burning was significantly higher. Patients had increased GMV and lower FA in the hippocampus (Hc), and decreased GMV in the medial prefrontal cortex (mPFC). rsfMRI revealed altered connectivity patterns in different states of pain/burning, with increased connectivity between mPFC (a node in the default mode network) and anterior cingulate cortex, occipital cortex, ventromedial PFC, and bilateral Hc/amygdala in the afternoon compared with the morning session. Furthermore, mPFC‐Hc connectivity was higher in BMS patients than control subjects for the afternoon but not the morning session. mPFC‐Hc connectivity was related to Beck depression inventory scores both between groups and between burning states within patients, suggesting that depression and anxiety partially explain pain‐related brain dysfunction in BMS. Overall, we provide multiple lines of evidence supporting aberrant structure and function in the mPFC and Hc, and implicate a circuit involving the mPFC and Hc in regulating mood and depressive symptoms in BMS.

Altered Brain Structure and Function Correlate with Disease Severity and Pain Catastrophizing in Migraine Patients

Our study provides a new and comprehensive look at how migraine affects brain structure, how these changes in structure are related to functional brain networks, and how coping and disease severity influence both structure and functional networks. Specifically, we demonstrate concomitant functional and structural brain changes related to pain catastrophizing and disease severity in migraine patients. Abstract Cover Figure Migraine patients (Pts) show widespread structural and functional brain changes that are associated with symptoms and increased pain catastrophizing A, Migraine patients showed (i) increased gray matter volume (GMV) in the left (L) hippocampus and (ii) decreased cortical thickness in the L anterior midcingulate cortex (aMCC) compared to healthy control subjects. B, Pain catastrophizing correlated with GMV reductions in the (i) L primary somatosensory cortex (S1) and (ii) L medial prefrontal cortex (mPFC), and cortical thinning in the (iii) L dorsolateral prefrontal cortex (DLPFC) and middle temporal gyrus (MTG) in migraine patients. C, GMV reductions correlated with (i) disease duration (ii), attack frequency, and (iii) migraine pain intensity in patients. D, Whole-brain overlay maps for migraine patients and healthy controls for the (i) L PCC, (ii) L aINS, and (iii) aMCC seed regions rendered onto inflated brains. Red represents resting-state functional connectivity for healthy controls and green represents the same maps in migraine patients. Yellow represents areas showing overlap in functional connectivity in controls and migraineurs. Images are thresholded at T = 4.5 (cluster extent = 25) for visualization purposes. The schematic illustrates the relationship between disease severity measures and pain catastrophizing and disruptions in functional connectivity between the default mode network (DMN), central executive network (CEN), and salience network (SN) in migraine patients. In patients, pain catastrophizing correlated with increased coupling between DMN and CEN nodes (PCC-DLPFC), whereas disease duration and migraine pain intensity correlated with SN-DMN network decoupling (aINS/aMCC-mPFC), and increased SN-CEN (aMCC-aINS) network coupling, respectively. To investigate the neuroanatomical and functional brain changes in migraine patients relative to healthy controls, we used a combined analytical approach including voxel- and surface-based morphometry along with resting-state functional connectivity to determine whether areas showing structural alterations in patients also showed abnormal functional connectivity. Additionally, we wanted to assess whether these structural and functional changes were associated with group differences in pain catastrophizing and migraine-related disease variables in patients. We acquired T1-weighted anatomical and functional magnetic resonance imaging scans during rest in human subjects with a diagnosis of migraine and healthy controls. Structural analyses revealed greater left hippocampal gray matter volume and reduced cortical thickness in the left anterior midcingulate in patients compared with controls. We also observed negative associations between pain catastrophizing and migraine disease variables and gray matter in areas implicated in processing the sensory, affective, and cognitive aspects of pain in patients. Functional connectivity analyses showed that migraine patients displayed disrupted connectivity between default mode, salience, cognitive, visuospatial, and sensorimotor networks, which was associated with group differences in pain catastrophizing and migraine-related disease variables in patients. Together, our findings show widespread morphological and functional brain abnormalities in migraineurs in affective, cognitive, visual, and pain-related brain areas, which are associated with increased pain catastrophizing, disease chronicity, and severity of symptoms, suggesting that these structural and functional changes may be a consequence of repeated, long-term nociceptive signaling leading to increased pain sensitivity, mood disturbances, and maladaptive coping strategies to deal with unrelenting pain.

Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: A longitudinal MRI study

Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague-Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7 T MRI scanner 1 week prior to (pre-injury) and 4 (early/subchronic) and 20 weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. (1)H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4 weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2 weeks pre-injury, and 2, 5, 9, 14, and 19 weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post-injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors.

Impaired Histatin-5 Levels and Salivary Antimicrobial Activity against C. albicans in HIV Infected Individuals

HIV-infected individuals constitute a population highly susceptible to opportunistic infections, particularly oral candidiasis caused by the most pathogenic human fungal species Candida albicans. Host-produced salivary antimicrobial peptides are considered to be an important part of the host innate immune system involved in protection of the oral cavity against colonization and infection by microbial species. Histatin-5 (Hst-5) specifically has exhibited potent anti-candidal properties in vitro. However, its importance in protecting the oral mucosa against candidal colonization and importantly, its contribution to the observed enhanced susceptibility of HIV-infected individuals to candidiasis has not been previously investigated. To that end, a novel immunoassay was used to demonstrate significant decrease in salivary Hst-5 levels in HIV+ individuals concomitant with enhanced candidal prevalence. Further, salivas anti-candidal potency was found to be proportional to Hst-5 concentration and significantly compromised in HIV+ subjects compared to controls. The key role for Hst-5 was further confirmed upon exposure to the Hst-5-specific antibody where salivas initial killing activity was substantially compromised. Combined, these findings identify Hst-5 as a key anti-candidal salivary component and demonstrate its decreased levels in HIV infection providing new insights into oral Innate immune defense mechanisms and the enhanced susceptibility of HIV+ individuals to oral candidiasis.

Periodontal Diseases: Bug Induced, Host Promoted

Periodontal disease (PD) is one of the most ubiquitous diseases of mankind, considered to be the second most common dental disease worldwide, after dental decay. This chronic condition is characterized by a complex group of inflammatory diseases affecting the periodontium, or the tissues that surround and support the teeth. If left untreated, this condition can lead to progressive loss of the alveolar bone around the teeth and subsequent loss of teeth. In fact, PD remains the most common cause of tooth loss in the world today; in the United States, it has a prevalence of 30%–50% of the population and can affect up to 90% of the population worldwide [1]. Like other conditions intimately related to access to hygiene and basic medical monitoring, periodontitis tends to be more common in economically disadvantaged populations. Interestingly, in addition to humans, periodontitis is the most common disease found in dogs affecting more than 80% of dogs aged three years or older. The complex nature of PD involving interactions between microbial and host factors has made this disease entity difficult to study. Here we provide a brief account of our current concepts of PD, its etiology, and the relevant clinical implications of this prevalent inflammatory disease.

Altered cognition-related brain activity and interactions with acute pain in migraine

Little is known about the effect of migraine on neural cognitive networks. However, cognitive dysfunction is increasingly being recognized as a comorbidity of chronic pain. Pain appears to affect cognitive ability and the function of cognitive networks over time, and decrements in cognitive function can exacerbate affective and sensory components of pain. We investigated differences in cognitive processing and pain–cognition interactions between 14 migraine patients and 14 matched healthy controls using an fMRI block-design with two levels of task difficulty and concurrent heat (painful and not painful) stimuli. Across groups, cognitive networks were recruited in response to a difficult cognitive task, and a pain–task interaction was found in the right (contralateral to pain stimulus) posterior insula (pINS), such that activity was modulated by decreasing the thermal pain stimulus or by engaging the difficult cognitive task. Migraine patients had less task-related deactivation within the left dorsolateral prefrontal cortex (DLPFC) and left dorsal anterior midcingulate cortex (aMCC) compared to controls. These regions have been reported to have decreased cortical thickness and cognitive-related deactivation within other pain populations, and are also associated with pain regulation, suggesting that the current findings may reflect altered cognitive function and top-down regulation of pain. During pain conditions, patients had decreased task-related activity, but more widespread task-related reductions in pain-related activity, compared to controls, suggesting cognitive resources may be diverted from task-related to pain-reduction-related processes in migraine. Overall, these findings suggest that migraine is associated with altered cognitive-related neural activity, which may reflect altered pain regulatory processes as well as broader functional restructuring.

High Frequency Migraine Is Associated with Lower Acute Pain Sensitivity and Abnormal Insula Activity Related to Migraine Pain Intensity, Attack Frequency, and Pain Catastrophizing

Migraine is a pain disorder associated with abnormal brain structure and function, yet the effect of migraine on acute pain processing remains unclear. It also remains unclear whether altered pain-related brain responses and related structural changes are associated with clinical migraine characteristics. Using fMRI and three levels of thermal stimuli (non-painful, mildly painful, and moderately painful), we compared whole-brain activity between 14 migraine patients and 14 matched controls. Although, there were no significant differences in pain thresholds nor in pre-scan pain ratings to mildly painful thermal stimuli, patients did have aberrant suprathreshold nociceptive processing. Brain imaging showed that, compared to controls, patients had reduced activity in pain modulatory regions including left dorsolateral prefrontal, posterior parietal, and middle temporal cortices and, at a lower-threshold, greater activation in the right mid-insula to moderate pain vs. mild pain. We also found that pain-related activity in the insula was associated with clinical variables in patients, including associations between: bilateral anterior insula and pain catastrophizing (PCS); bilateral anterior insula and contralateral posterior insula and migraine pain intensity; and bilateral posterior insula and migraine frequency at a lower-threshold. PCS and migraine pain intensity were also negatively associated with activity in midline regions including posterior cingulate and medial prefrontal cortices. Diffusion tensor imaging revealed a negative correlation between fractional anisotropy (a measure of white matter integrity; FA) and migraine duration in the right mid-insula and a positive correlation between left mid-insula FA and PCS. In sum, while patients showed lower sensitivity to acute noxious stimuli, the neuroimaging findings suggest enhanced nociceptive processing and significantly disrupted modulatory networks, particularly involving the insula, associated with indices of disease severity in migraine.