Papers by David M. Niddam
Cephalalgia, 2024
Background: The visual cortex is involved in the generation of migraine aura. Voxel-based multiva... more Background: The visual cortex is involved in the generation of migraine aura. Voxel-based multivariate analyses applied to this region may provide complementary information about aura mechanisms relative to the commonly used massunivariate analyses. Methods: Structural images constrained within the functional resting-state visual networks were obtained in migraine patients with (n ¼ 50) and without (n ¼ 50) visual aura and healthy controls (n ¼ 50). The masked images entered a multivariate analysis in which Gaussian process classification was used to generate pairwise models. Generalizability was assessed by five-fold cross-validation and non-parametric permutation tests were used to estimate significance levels. A univariate voxel-based morphometry analysis was also performed. Results: A multivariate pattern of grey matter voxels within the ventral medial visual network contained significant information related to the diagnosis of migraine with visual aura (aura vs. healthy controls: classification accuracy ¼ 78%, p < 0.001; area under the curve ¼ 0.84, p < 0.001; migraine with aura vs. without aura: classification accuracy ¼ 71%, p < 0.001; area under the curve ¼ 0.73, p < 0.003). Furthermore, patients with visual aura exhibited increased grey matter volume in the medial occipital cortex compared to the two other groups. Conclusions: Migraine with visual aura is characterized by multivariate and univariate patterns of grey matter changes within the medial occipital cortex that have discriminative power and may reflect pathological mechanisms.
Cephalalgia, 2020
We read the comments to our paper published in Cephalalgia (1) with great interest. In his commen... more We read the comments to our paper published in Cephalalgia (1) with great interest. In his comments, Dr. Ostojic (2) suggests that the reduced thalamic total creatine levels we observed in chronic migraine (CM) patients could potentially be remediated with oral creatine supplementation. It was further suggested that this could lead to a reduction in migraine symptoms. Dr. Ostojic nicely lists several potential hurdles that may have to be overcome for the therapy to be successful in CM patients. Here, we wish to further elaborate on the proposition put forward by Dr. Ostojic. Oral creatine supplementation for 2–4 weeks may increase brain creatine levels by about 8–15% in healthy adults (3,4), with the highest increase observed in the thalamus after 4 weeks of continuous administration (3). These results, however, should be interpreted with caution as they need to be confirmed in a larger study cohort. In our study, total creatine levels were reduced by about 10% (6.34 mM vs. 7.04 mM) in CM patients. Hence, the magnitude of the required change is within the range obtainable with oral supplementation. Furthermore, it has been suggested that the effects of creatine supplementation on brain function could be larger in conditions with chronic depletion of brain creatine (5). Modulation of thalamic creatine levels by supplementation furthermore has the potential to answer whether the observed total creatine reduction is a consequence of the headaches or if it contributes directly to generation or maintenance of the headaches. It would also be possible to examine whether the reduced total creatine levels are coupled to the concomitant reductions in thalamic total N-acetylaspartate observed in our study; that is, whether altered energy homeostasis leads to compromised neuronal health. It is noteworthy that a study on creatine supplementation in CM would have to control for the diet (vegetarian vs. non-vegetarian) and exercise patterns, as both can influence the available creatine levels (5). Finally, the long-term effects of creatine supplementation on endogenous creatine synthesis in the brain remains largely unknown and require further studies. Declaration of conflicting interests
Headache, 2023
Objective: To determine whether multivariate pattern regression analysis based on gray matter (GM... more Objective: To determine whether multivariate pattern regression analysis based on gray matter (GM) images constrained to the sensorimotor network could accurately predict trigeminal heat pain sensitivity in healthy individuals. Background: Prediction of individual pain sensitivity is of clinical relevance as high pain sensitivity is associated with increased risks of postoperative pain, pain chronification, and a poor treatment response. However, as pain is a subjective experience
Cephalalgia, 2023
Background: Medication overuse headache shares several characteristics with substance use disorde... more Background: Medication overuse headache shares several characteristics with substance use disorders. However, key features of substance use disorders such as increased impulsivity and alterations in reward processing remain little explored in medication overuse headache. Methods: Temporal discounting and impulsive decision making behavior and the associated brain mechanisms were assessed in 26 chronic migraine patients with medication overuse headache and in 28 healthy controls. Regionsof-interest analyses were first performed for task-related regions, namely the ventral striatum and the ventromedial and dorsomedial prefrontal cortices. Resting-state functional connectivity between these regions were then explored. An additional 27 chronic migraine patients without medication overuse headache were included for comparison in the latter analysis. Results: Patients with medication overuse headache showed steeper temporal discounting behavior than healthy controls. They also showed weaker subjective value representations in the dorsomedial prefrontal cortex, when accepting larger delayed rewards, and in ventral striatum and ventromedial prefrontal cortex, when accepting the smaller immediate reward. Resting-state functional connectivity was reduced among the valuation regions when comparing patients with medication overuse headache to the other two control groups. Conclusions: Patients with medication overuse headache were characterized by altered processing and dysconnectivity in the reward system during intertemporal choices and in the resting-state.
PAIN, 2021
The primary somatosensory cortex (SI) is a critical part of the neural substrate underlying inter... more The primary somatosensory cortex (SI) is a critical part of the neural substrate underlying interindividual differences in pain sensitivity. Here, we investigated whether resting-state functional connectivity, gray matter density (GMD), and GABA and Glx (glutamate and glutamine) levels of the sensorimotor cortices were related to pain thresholds and whether such imaging measures could predict high and low pain sensitivity. Functional, structural, and spectroscopic magnetic resonance data were obtained from 48 healthy participants together with pain thresholds of the right index finger. Left and right sensorimotor networks (SMN) were extracted by means of independent component analysis, and GMD was measured within the combined SMN by means of voxel-based morphometry. Spectroscopic data were acquired from the bilateral sensorimotor cortices. Within the left SMN, functional connectivity to the right SI correlated positively with pain thresholds. In addition, GMD in the left SI and the GABA laterality index correlated positively with pain thresholds. A positive correlation was also found between the GABA laterality index and the left SMN connectivity to the right SI. Finally, the above mentioned functional connectivity and GMD measures could correctly predict high and low pain sensitivity in 83.7% of the study population. In summary, we showed that interindividual differences in pain sensitivity were related to the resting-state functional connectivity, interhemispheric GABA tone, and GMD of the sensorimotor cortices. Furthermore, high and low pain sensitivity could be predicted with high accuracy using imaging measures from the primary sensorimotor cortices.
Curr Pain Headache Rep. , 2020
Purpose of Review The purpose of this paper is to review and synthesize current literature in whi... more Purpose of Review The purpose of this paper is to review and synthesize current literature in which neurochemical and structural brain imaging were used to investigate chronic migraine (CM) pathophysiology and to further discuss the clinical implications. Recent Findings Spectroscopic and structural MRI studies have shown the presence of both impaired metabolism and structural alterations in the brain of CM patients. Metabolic changes in key brain regions support the notion of altered energetics and homeostasis as part of CM pathophysiology. Furthermore, CM, like other chronic pain disorders, may undergo structural reorganization in pain-related brain regions following near persistent endogenous painful input. Finally, both imaging techniques may provide potential biomarkers of disease state and progression and may help guide novel therapeutic interventions or strategies. Summary Spectroscopic and structural MRI have revealed novel aspects of CM pathophysiology. Findings from the former support the metabolic theory of migraine pathogenesis.
Cephalalgia, 2020
Background: Medication overuse headache may be associated with widespread alterations along the t... more Background: Medication overuse headache may be associated with widespread alterations along the thalamocortical pathway, a pathway involved in pain perception and disease progression. This study addressed whether brain metabolites in key regions of the thalamocortical pathway differed between chronic migraine patients with medication overuse headache and without medication overuse headache. Methods: Magnetic resonance spectroscopic imaging was used to map metabolites in the bilateral anterior cingulate cortices, mid cingulate cortices, posterior cingulate cortices, and the thalami. Sixteen patients with medication overuse headache were compared with 16 matched patients without medication overuse headache and 16 matched healthy controls. Results: Glutamate and glutamine in the right mid cingulate cortex and myo-inositol in the left anterior cingulate cortex were significantly higher in patients with medication overuse headache than patients without medication overuse headache , but similar to healthy controls. Both patient groups exhibited reduced N-acetyl-aspartate and creatine in the thalamus, reduced myo-inositol in the right anterior cingulate cortex, and elevated choline in the right mid cingulate cortex. Finally, a negative association between myo-inositol laterality index in the anterior cingulate cortices and number of days per month with acute medication use was found across all patients. Conclusions: Patients with medication overuse headache were characterized by a distinct concentration profile of myo-inositol, a glial marker, in the anterior cingulate cortices that may have arisen from medication overuse and could contribute to the development of medication overuse headache.
Shoulder pain is a common condition associated with slow recovery and high recurrence rates. Pers... more Shoulder pain is a common condition associated with slow recovery and high recurrence rates. Persistent pain may lead to structural brain changes that may further promote pain chronification. The present study addressed whether abnormal changes in cortical surface structure exist in patients with chronic shoulder pain of myofascial origin and whether such changes would be related to pain measures. Brain structural MRIs were obtained in 22 patients with chronic pain in the bilateral upper trapezius muscles and in 22 healthy controls. Cortical thickness, gyrification index and sulcal depth were assessed together with pain measures. Shallower sulcal depth was found in patients in the right central sulcus, posterior insula, inferior frontal and dorsomedial prefrontal cortices, precuneus, and the middle temporal cortex, and in the left medial orbitofrontal cortex. Negative correlations were found between the right central sulcus and pain intensity and between the left medial orbitofrontal cortex and pain affect. Cortical thickness or gyrification index did not differ significantly between the two groups. The afflicted cortical regions constitute interacting networks responsible for sensory, affective and cognitive dimensions of the pain experience.
Pain, 2013
Dysmenorrhea is the most prevalent gynecological disorder in women of child-bearing age. Dysmenor... more Dysmenorrhea is the most prevalent gynecological disorder in women of child-bearing age. Dysmenorrhea is associated with central sensitization and functional and structural changes in the brain. Our recent brain morphometry study disclosed that dysmenorrhea is associated with trait-related abnormal gray matter (GM) changes, even in the absence of menstrual pain, indicating that the adolescent brain is vulnerable to menstrual pain. Here we report rapid state-related brain morphological changes, ie, between pain and pain-free states, in dysmenorrhea. We used T1-weighted anatomic magnetic resonance imaging to investigate regional GM volume changes between menstruation and periovulatory phases in 32 dysmenorrhea subjects and 32 age- and menstrual cycle-matched asymptomatic controls. An optimized voxel-based morphometry analysis was conducted to disclose the possible state-related regional GM volume changes across different menstrual phases. A correlation analysis was also conducted between GM differences and the current menstrual pain experience in the dysmenorrhea group. Compared with the periovulatory phase, the dysmenorrhea subjects revealed greater hypertrophic GM changes than controls during the menstruation phase in regions involved in pain modulation, generation of the affective experience, and regulation of endocrine function, whereas atrophic GM changes were found in regions associated with pain transmission. Volume changes in regions involved in the regulation of endocrine function and pain transmission correlated with the menstrual pain experience scores. Our results demonstrated that short-lasting cyclic menstrual pain is associated not only with trait-related but also rapid state-related structural alterations in the brain. Considering the high prevalence rate of menstrual pain, these findings mandate a great demand to revisit dysmenorrhea with regard to its impact on the brain and other clinical pain conditions.
Pain, 2012
Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patie... more Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsychological mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion-/conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal distension-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients.
Lasers in Medical Science, 2014
The aim of this study was to investigate the autonomic responses and central manifestations by pe... more The aim of this study was to investigate the autonomic responses and central manifestations by peripheral FIR stimulation. Ten subjects (mean ± SD age 26.2 ± 3.52 years) received FIR stimulation at left median nerve territory for 40 min. Electrocardiograph was continuously recorded and heart rate variability (HRV) were analyzed. By using a 3 T-MRI scanner, three sessions of resting-state functional magnetic resonance images (fMRI) were acquired, namely, before (baseline-FIR), immediately after (IA-FIR) and 15 min after FIR was turned off (Post-FIR). The fractional amplitude of low-frequency (0.01-0.08 Hz) fluctuation (fALFF) of each session to evaluate the intensity of resting-brain activity in each session was analyzed. Our results showed that FIR stimulation induced significant HRV responses such as an increasing trend of nLF and LF/HF ratio, while FIR increased fALFF in right superior front gyrus, middle frontal gyrus and decreased the resting brain activity at fusiform gyrus, extrastriae cortex, inferior temporal gyrus and middle temporal gyrus, especially 15 min after FIR was turned off. We conclude that the central manifestation and the autonomic responses are prominent during and after FIR stimulation, which provide important mechanistic explanation on human disorder treated by such energy medicine.
Lasers in Surgery and Medicine, 2011
Kenalog application onto surgical wounds has been used to control dynamic pain following Laser-As... more Kenalog application onto surgical wounds has been used to control dynamic pain following Laser-Assisted-Uvulo-Palatoplasty (LAUP) with good results in our department. When the effect was sub-optimal, insufficient ointment over the superior-lateral corner of wounds were always noted. Fulfilling the coating led to optimal results, and preliminary trials showed a good outcome of dynamic pain control as well by treating the corners only. The corners were thus named &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;sweet spots.&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; This study aimed to verify the efficacy of applying Kenalog on &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;sweet spots&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; instead of whole surgical wounds to mitigate dynamic pain due to LAUP. This is an outcomes research. Fifty-five subjects with primary snoring treated with LAUP were studied. By using Kenalog, local treatments were applied to sweet spots during the first postoperative week. A visual analogous scale was used to evaluate dynamic pain on the 1st, 2nd, 3rd, and 7th days after LAUP. Once sweet spots were treated, there was instant alleviation of dynamic pain; the average improvement level was ≥80% (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001, power = 100%). The area of sweet spots, in contrast to the significant relief in dynamic pain, occupied only about 30% of denuded mucosa. Dynamic pain after LAUP could immediately be mitigated by local treatments upon sweet spots using topical regimens. The large-scale relief of dynamic pain in contrast to the small area of sweet spots implies a congregation of free nerve endings there. Our finding invites further studies to correlate the neuroanatomy of the soft palate and dynamic pain caused by LAUP.
Migraine chronification is associated with a dysfunctional thalamocortical pathway. The present s... more Migraine chronification is associated with a dysfunctional thalamocortical pathway. The present study addressed whether abnormal concentrations of neurochemicals exist in key brain regions of this pathway in chronic migraine. Magnetic resonance spectroscopic imaging of the bilateral medial walls of the brain was used to measure choline, creatine, glutamate and glutamine, myo-inositol, and N-acetyl-aspartate in chronic migraine patients and in matched groups of episodic migraine patients and healthy controls. A region of interest analysis was conducted to examine whether N-acetyl-aspartate, a marker of neuronal integrity, was reduced in the thalamus, occipital cortex and anterior cingulate cortex in chronic migraine. Interregional N-acetyl-aspartate correlations among these regions of interest were also examined. Additionally, statistical mapping was performed for all the metab-olites throughout the medial walls. Chronic migraine was associated with N-acetyl-aspartate reductions in the bilateral thalami and in the right anterior cingulate. The N-acetyl-aspartate reduction in the right thalamus correlated with disease duration. Compared with healthy controls, patients with chronic migraine had altered interregional N-acetyl-aspartate correlations between the right thalamus–anterior cingulate and thalamus–occipital cortex, and between the left and right anterior cingulate. N-acetyl-aspartate concentrations and interregional correlations in patients with episodic migraine were between those of healthy controls and chronic migraine patients. The unconstrained analyses revealed a reduction of myo-inositol in the left anterior and posterior cingulate in both patient groups as well as a negative association with depression scores for the anterior cingulate in the combined patient group. In addition, migraine patients with headache on the scan day (irrespective of diagnosis) had reduced N-acetyl-aspartate and total creatine concentrations in the right dorsal anterior cingulate. Reduced N-acetyl-aspartate metabolism and altered interregional N-acetyl-aspartate correlations lend support to the role of thalamocortical dysfunction in migraine chronification. It remains to be established if the pattern of changes within the N-acetyl-aspartate network is specific to chronic migraine or can be found in other chronic pain conditions.
Background: Myofascial trigger points (MTrPs) are a highly prevalent source of musculoskeletal pa... more Background: Myofascial trigger points (MTrPs) are a highly prevalent source of musculoskeletal pain. Prolonged ongoing nociceptive input from MTrPs may lead to maladaptive changes in the central nervous system. It remains, however, unknown whether pain from MTrPs is associated with brain atrophy. In addition, stress, which may contribute to the formation of MTrPs, is also known to affect brain structures. Here, we address whether structural brain changes occur in patients with chronic pain originating from MTrPs and whether such changes are related to pain or stress. Methods: Voxel-based morphometry was used to compare grey-matter (GM) volumes in 21 chronic pain patients, with MTrPs in the bilateral upper trapezius muscles, with 21 healthy controls. Hyperalgesia was assessed by pressure pain thresholds, and stress was assessed by cortisol levels and anxiety questionnaires. Results: Patients exhibited normal stress levels but lowered pain thresholds. GM atrophy was found in dorsal and ventral prefrontal regions in patients. The GM density of the right dorsolateral prefrontal cortex correlated with pain thresholds in patients, i.e. the more atrophy, the lower pain threshold. GM atrophy was also found in the anterior hippocampus, but the atrophy was neither related to pain nor stress. Conclusions: Patients with chronic myofascial pain exhibit GM atrophy in regions involved in top-down pain modulation and in processing of negative affect. The relationship between the dorsolateral prefrontal cortex and pain thresholds suggests the presence of pain disinhibition. No evidence was found for the involvement of stress. It remains unclear whether the observed atrophy contributes to the development of the chronic pain state or is caused by the ongoing nociceptive input. Significance: Chronic myofascial pain, caused by myofascial trigger points, is associated with localized brain atrophy in areas involved in pain processing and modulation, among others. These findings extend previous knowledge about peripheral and spinal changes to the supraspinal level.
Brain Research, 2013
Emotional distress a b s t r a c t Brain activity resulting from changes in pain intensity may no... more Emotional distress a b s t r a c t Brain activity resulting from changes in pain intensity may not only reflect changes in stimulus intensity but also in emotional distress. The anterior and mid-posterior insula have been associated with anticipatory anxiety and sensory-discrimination, respectively.
Neuropsychologia, Jan 26, 2014
When the pain intensity of an impending stimulus is highly unpredictable, the uncertain expectati... more When the pain intensity of an impending stimulus is highly unpredictable, the uncertain expectation of pain may exacerbate the perceived pain intensity of the stimulus, compared to the same stimulus delivered with certain expectation. Here, we address how the perception of physically identical stimuli delivered with different predictability of the pain intensity is influenced by learning. We hypothesized that the difference in perceived pain intensity following high and low predictable cues could be explained by: (1) uncertainty-driven hyperalgesia associated with hippocampal activity; (2) certainty-driven hypoalgesia associated with activity in the periaqueductal gray (PAG) and the rostral anterior cingulate cortex (rACC); and (3) a mixed model of both. To test this hypothesis, two sessions of a delayed conditioning paradigm was employed in conjunction with event-related functional magnetic resonance imaging and trial-by-trial rating of the pain intensity. Participants had to simul...
Uploads
Papers by David M. Niddam