Exploring cortical morphology biomarkers of amnesic mild cognitive impairment using novel fractal dimension-based structural MRI analysis.

Amnestic mild cognitive impairment (aMCI) is considered as an intermediate stage of Alzheimer's disease, but no MRI biomarkers currently distinguish aMCI from healthy individuals effectively. Fractal dimension, a quantitative parameter, provides superior morphological information compared to conventional cortical thickness methods. Few studies have used cortical fractal dimension values to differentiate aMCI from healthy controls. In this study, we aim to build an automated discriminator for accurately distinguishing aMCI using fractal dimension measures of the cerebral cortex. Thirty aMCI patients and 30 health controls underwent structural MRI of the brain. First, the atrophy of participants' cortical sub-regions of Desikan-Killiany cortical atlas was assessed using fractal dimension and cortical thickness. The fractal dimension is more sensitive than cortical thickness in reducing dimensional effects and may accurately reflect morphological changes of the cortex in aMCI. The aMCI group had significantly lower fractal dimension values in the bilateral temporal lobes, right limbic lobe and right parietal lobe, whereas they showed significantly lower cortical thickness values only in the bilateral temporal lobes. Fractal dimension analysis was able to depict most of the significantly different focal regions detected by cortical thickness, but additionally with more regions. Second, applying the measured fractal dimensions (and cortical thickness) of both cerebral hemispheres, an unsupervised discriminator was built for the aMCI and healthy controls. The proposed fractal dimension-based method achieves 80.54% accuracy in discriminating aMCI from healthy controls. The fractal dimension appears to be a promising biomarker for cortical morphology changes that can discriminate patients with aMCI from healthy controls.

Can transcranial direct current stimulation combined with interactive computerized cognitive training boost cognition and gait performance in older adults with mild cognitive impairment? a randomized controlled trial.

BACKGROUND: Older adults with Mild Cognitive Impairment (MCI) are often subject to cognitive and gait deficits. Interactive Computerized Cognitive Training (ICCT) may improve cognitive function; however, the effect of such training on gait performance is limited. Transcranial Direct Current Stimulation (tDCS) improves cognition and gait performance. It remains unclear whether combining tDCS with ICCT produces an enhanced synergistic effect on cognition and complex gait performance relative to ICCT alone. This study aimed to compare the effects of tDCS combined with ICCT on cognition and gait performance in older adults with MCI. METHOD: Twenty-one older adults with MCI were randomly assigned to groups receiving either anodal tDCS and ICCT ( tDCS + ICCT ) or sham tDCS and ICCT ( sham + ICCT ). Participants played Nintendo Switch cognitive games for 40 min per session, simultaneously receiving either anodal or sham tDCS over the left dorsolateral prefrontal cortex for the first 20 min. Cognitive and gait assessments were performed before and after 15 training sessions. RESULTS: The global cognition, executive function, and working-memory scores improved in both groups, but there were no significant interaction effects on cognitive outcomes. Additionally, the group × time interactions indicated that tDCS + ICCT significantly enhanced dual-task gait performance in terms of gait speed (p = 0.045), variability (p = 0.016), and dual-task cost (p = 0.039) compared to sham + ICCT. CONCLUSION: The combined effect of tDCS and ICCT on cognition was not superior to that of ICCT alone; however, it had a significant impact on dual-task gait performance. Administering tDCS as an adjunct to ICCT may thus provide additional benefits for older adults with MCI. TRIAL REGISTRATION: This trial was registered at http://www. CLINICALTRIALS: in.th/ (TCTR 20,220,328,009).

Decision-making impairment under ambiguity but not under risk may underlie medication overuse in patients with chronic migraine.

OBJECTIVE: To explore whether patients with chronic migraine and medication overuse headache (CM + MOH) present with decision-making deficit. BACKGROUND: Factors underlying MOH in patients with CM remain unclear. Whether the process of decision-making plays a role in MOH is still controversial. Decision-making varies in the degree of uncertainty: under ambiguity where the probability of outcome is unknown, and under risk where probabilities are known. METHODS: Decisions under ambiguity and risk were assessed with the Iowa Gambling Task and the Cambridge Gambling Task, respectively, whereas executive function was assessed by the Wisconsin Card Sorting Test. RESULTS: A total of 75 participants: 25 patients with CM + MOH, 25 with CM, and 25 age- and sex-similar healthy controls (HCs), completed this cross-sectional study. There was no significant difference in headache profiles except for more frequent analgesic use (mean ± SD: 23.5 ± 7.6 vs. 6.8 ± 3.4 days; p < 0.001) and higher Severity of Dependence Scores (median [25th-75th percentile]: 8 [5-11] vs. 1 [0-4]; p < 0.001) in patients with CM + MOH compared to CM. Total net score (mean ± SD) on the Iowa Gambling Task in patients with CM + MOH, CM, and HCs were - 8.1 ± 28.7, 10.9 ± 29.6, and 14.2 ± 28.8, respectively. There was a significant difference between the three groups (F(2, 72) = 4.28, p = 0.017), with patients with CM + MOH making significantly more disadvantageous decisions than patients with CM (p = 0.024) and HCs (p = 0.008), while the CM and HC groups did not differ (p = 0.690). By contrast, there was no significant difference between the groups in the Cambridge Gambling Task and the Wisconsin Card Sorting Test. Furthermore, performance on the Iowa Gambling Task was inversely correlated with analgesic consumption (r = -0.41, p = 0.003), suggesting that decision-making under ambiguity may be related to MOH. CONCLUSIONS: Our data suggest that patients with CM + MOH had impaired decisions under ambiguous, but not risky situations. This dissociation indicates disrupted emotional feedback processing rather than executive dysfunction, which may underlie the pathogenesis of MOH.

2022 Taiwan Guidelines for Acute Treatment of Migraine.

The Taiwan Headache Society published its guidelines for acute migraine treatment in 2017. Since then, emerging drugs and treatment options have developed rapidly. The migraine-specific drugs gepants and ditans and several noninvasive neuromodulation devices have been approved for use in Europe and the United States. Although not all emerging drugs and treatment options have been approved for use in Taiwan, keeping pace with international trends and updating treatment guidelines are imperative. Therefore, the Treatment Guideline Subcommittee of the Taiwan Headache Society reviewed the quality of recent trials, evaluated the corresponding grade of evidence, and appraised the reported clinical efficacy to reach a new consensus. To ensure that the updated Taiwan guidelines are appropriate and feasible, the subcommittee also referred to the guidelines from the United States, Europe, Canada, and other countries concerning the main roles, recommendation levels, clinical efficacy, and adverse reactions of drugs for the acute migraine treatment. Several types of drugs are currently available for acute migraine treatment in Taiwan. These drugs can be categorized into migraine-specific and migraine-non-specific. Among them, migraine-specific triptans (oral or nasal spray formulations) and migraine-nonspecific acetaminophen and NSAIDs (diclofenac, ibuprofen, naproxen) are highly recommended because they are supported by strong evidence and demonstrate high efficacy. Prochlorperazine injection has been upgraded to a highly recommended level because of the rich clinical experience for this treatment. Ergotamine/caffeine remains a second-line drug because of its lower specificity and efficacy compared with triptans. High-dose aspirin was downgraded to rescue treatment because of potential gastrointestinal side effects. Although evidence supports the combination of oral tramadol and acetaminophen, this combination should be used as a rescue treatment due to concerns about dependence. Evidence supporting the use of intravenous tramadol or morphine is insufficient; therefore, their use is not recommended. As for non-pharmacological approaches, there are only limited controlled data. The choice of treatment for acute migraine attacks should follow the concept of "stratified care." For mild to moderate migraine attacks, oral NSAIDs are the first choice, with combination analgesics, intravenous/intramuscular NSAIDs as alternatives. For moderate to severe attacks, oral or nasal spray triptans and ergotamine/caffeine compounds are recommended and should be administered in the early stage of migraine attacks. Antiemetics can be used as supplements to alleviate nausea and vomiting. Other emerging migraine-specific drugs, such as gepants or ditans, may also have a role in the future. Notably, a combination of a triptan and a NSAID yielded a better efficacy compared with either therapy alone. Parenteral steroids and fluid supply are the first-line treatment for status migrainosus. Acetaminophen is suitable for mild to moderate migraine attacks and remains the first choice for children and pregnant women. To prevent medication overuse headache, the use of acute treatment should be limited to a maximum of 2 days per week. Key words: acute migraine treatment, evidence-based medicine, treatment guidelines, triptans, ergotamine, neuromodulation.

High-Frequency External Muscle Stimulation Reduces Depressive Symptoms in Older Male Veterans: A Pilot Study.

OBJECTIVE: Late-life depression (LLD) is a severe public health problem. Given that pharmacological treatments for LLD are limited by their side effects, development of efficient and tolerable nonpharmacological treatment for LLD is urgently required. This study investigated whether high-frequency external muscle stimulation could reduce depressive symptoms in LLD. METHODS: Twenty-two older male veterans with major depression were recruited and randomized into a treatment (n = 9) or sham control group (n = 13). The groups received high-frequency external muscle stimulation or sham intervention 3 times per week for 12 weeks. Clinical symptoms and muscle strength were evaluated at baseline and every 2 weeks. RESULTS: The 2 groups were homogeneous in age, baseline clinical symptoms, and muscle strength. The treatment group showed significant improvement in depression and anxiety scores and muscle strength (all P < .01), whereas the control group showed no significant change after the 12-week follow-up. Compared to the control group, the treatment group showed significant improvements in depression (Geriatric Depression Scale, P = .009; Hamilton Depression Rating Scale, P = .007) and anxiety scores (HAMA, P = .008) and muscle strength (all P < .001). Changes in depression and anxiety levels were significantly correlated with changes in muscle strength after the study. In the treatment group, we observed a trend of correlation between the reduction in depression and muscle strength gains. CONCLUSION: High-frequency external muscle stimulation appears to be an effective treatment for older patients with LLD. Large studies with more tests and/or conducted in different populations are warranted to validate these preliminary findings.

Group Music Intervention Using Percussion Instruments to Reduce Anxiety Among Elderly Male Veterans with Alzheimer Disease.

BACKGROUND This study aimed to assess the impact of a group music intervention on anxiety and depression of elderly male veterans with dementia. MATERIAL AND METHODS In total, 50 elderly men with Alzheimer disease were randomly divided into intervention and control groups. Patients in the intervention group attended a 60-minute group music session that used percussion instruments with familiar music in the morning once a week for 12 weeks, whereas those in the control group received a rest and reading session at the same intervals and under the same conditions. The Hamilton Anxiety Rating Scale and Geriatric Depression Scale were used to assess anxiety and depression at baseline, week 6, and week 12. The Primary Measures of Music Audiation (PMMA) was used to assess musical aptitude at the baseline. RESULTS A significant reduction in the anxiety level following the 12-week music sessions was observed in the intervention group (P<.001), but there was no significant change in the control group. However, the change in depressive symptoms between the 2 groups was nonsignificant. In the intervention group, when stratifying patients based on music aptitude determined through PMMA assessment, patients with high PMMA scores had significantly reduced anxiety symptoms over time compared with those with low scores. CONCLUSIONS For elderly male veterans with dementia, participating in a group music intervention reduced anxiety symptoms. In patients with high musical aptitude, the treatment effects on anxiety reduction were satisfactory. Measures of music aptitude may provide valuable information regarding patients' response to music intervention.

Alteration of the Intra- and Inter-Lobe Connectivity of the Brain Structural Network in Normal Aging.

The morphological changes in cortical parcellated regions during aging and whether these atrophies may cause brain structural network intra- and inter-lobe connectivity alterations are subjects that have been minimally explored. In this study, a novel fractal dimension-based structural network was proposed to measure atrophy of 68 parcellated cortical regions. Alterations of structural network parameters, including intra- and inter-lobe connectivity, were detected in a middle-aged group (30-45 years old) and an elderly group (50-65 years old). The elderly group exhibited significant lateralized atrophy in the left hemisphere, and most of these fractal dimension atrophied regions were included in the regions of the "last-in, first-out" model. Globally, the elderly group had lower modularity values, smaller component size modules, and fewer bilateral association fibers. They had lower intra-lobe connectivity in the frontal and parietal lobes, but higher intra-lobe connectivity in the temporal and occipital lobes. Both groups exhibited similar inter-lobe connecting pattern. The elderly group revealed separations, sparser long association fibers, commissural fibers, and lateral inter-lobe connectivity lost effect, mainly in the right hemisphere. New wiring and reconfiguring modules may have occurred within the brain structural network to compensate for connectivity, decreasing and preventing functional loss in cerebral intra- and inter-lobe connectivity.

Angiotensin-converting enzyme inhibitors and bacterial pneumonia in patients with Parkinson disease.

BACKGROUND: To evaluate the association of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with pneumonia development in patients with Parkinson's disease (PD). METHODS: The study cohort consisted of patients aged 50 years or older who were initially diagnosed with PD and had hypertension. We assessed the patients' exposure statuses and accumulated doses of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. We then evaluated the risk of pneumonia development in the patients who were exposed to these drugs and those who were not. RESULTS: We examined 2,310 patients. During the observation period, 608 patients developed pneumonia. Angiotensin-converting enzyme inhibitors were associated with a lower risk of pneumonia. This association was dose-dependent. CONCLUSION: Angiotensin-converting enzyme inhibitor use was associated with a dose-dependent reduction in the risk of pneumonia in patients with PD and hypertension.

Altered neurochemical coupling in the occipital cortex in migraine with visual aura.

BACKGROUND: Visual aura is present in about one-third of migraine patients and triggering by bright or flickering lights is frequently reported. METHOD: Using migraine with visual aura patients, we investigated the neurochemical profile of the visual cortex using magnetic resonance spectroscopy. Specifically, glutamate/creatine and GABA/creatine ratios were quantified in the occipital cortex of female migraine patients. RESULTS: GABA levels in the occipital cortex of migraine patients were lower than that of controls. Glutamate levels in migraine patients, but not controls, correlated with the blood-oxygenation-level-dependent (BOLD) signal in the primary visual cortex during visual stimulation. CONCLUSION: Migraine with visual aura appears to disrupt the excitation-inhibition coupling in the occipital cortex.

Does the dopamine hypothesis explain schizophrenia?

The dopamine hypothesis has been the cornerstone in the research and clinical practice of schizophrenia. With the initial emphasis on the role of excessive dopamine, the hypothesis has evolved to a concept of combining prefrontal hypodopaminergia and striatal hyperdopaminergia, and subsequently to the present aberrant salience hypothesis. This article provides a brief overview of the development and evidence of the dopamine hypothesis. It will argue that the current model of aberrant salience explains psychosis in schizophrenia and provides a plausible linkage between the pharmacological and cognitive aspects of the disease. Despite the privileged role of dopamine hypothesis in psychosis, its pathophysiological rather than etiological basis, its limitations in defining symptoms other than psychosis, as well as the evidence of other neurotransmitters such as glutamate and adenosine, prompt us to a wider perspective of the disease. Finally, dopamine does explain the pathophysiology of schizophrenia, but not necessarily the cause per se. Rather, dopamine acts as the common final pathway of a wide variety of predisposing factors, either environmental, genetic, or both, that lead to the disease. Other neurotransmitters, such as glutamate and adenosine, may also collaborate with dopamine to give rise to the entire picture of schizophrenia.

Decreased Brain Structural Network Connectivity in Patients with Mild Cognitive Impairment: A Novel Fractal Dimension Analysis.

Mild cognitive impairment (MCI) is widely regarded to be the intermediate stage to Alzheimer's disease. Cerebral morphological alteration in cortical subregions can provide an accurate predictor for early recognition of MCI. Thirty patients with MCI and thirty healthy control subjects participated in this study. The Desikan-Killiany cortical atlas was applied to segment participants' cerebral cortex into 68 subregions. A complexity measure termed fractal dimension (FD) was applied to assess morphological changes in cortical subregions of participants. The MCI group revealed significantly decreased FD values in the bilateral temporal lobes, right parietal lobe including the medial temporal, fusiform, para hippocampal, and also the orbitofrontal lobes. We further proposed a novel FD-based brain structural network to compare network parameters, including intra- and inter-lobular connectivity between groups. The control group had five modules, and the MCI group had six modules in their brain networks. The MCI group demonstrated shrinkage of modular sizes with fewer components integrated, and significantly decreased global modularity in the brain network. The MCI group had lower intra- and inter-lobular connectivity in all lobes. Between cerebral lobes, the MCI patients may maintain nodal connections between both hemispheres to reduce connectivity loss in the lateral hemispheres. The method and results presented in this study could be a suitable tool for early detection of MCI.

Abnormalities of Hippocampal Subfield and Amygdalar Nuclei Volumes and Clinical Correlates in Behavioral Variant Frontotemporal Dementia with Obsessive-Compulsive Behavior-A Pilot Study.

(1) Background: The hippocampus (HP) and amygdala are essential structures in obsessive-compulsive behavior (OCB); however, the specific role of the HP in patients with behavioral variant frontotemporal dementia (bvFTD) and OCB remains unclear. (2) Objective: We investigated the alterations of hippocampal and amygdalar volumes in patients with bvFTD and OCB and assessed the correlations of clinical severity with hippocampal subfield and amygdalar nuclei volumes in bvFTD patients with OCB. (3) Materials and methods: Eight bvFTD patients with OCB were recruited and compared with eight age- and sex-matched healthy controls (HCs). Hippocampal subfield and amygdalar nuclei volumes were analyzed automatically using a 3T magnetic resonance image and FreeSurfer v7.1.1. All participants completed the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Neuropsychiatric Inventory (NPI), and Frontal Behavioral Inventory (FBI). (4) Results: We observed remarkable reductions in bilateral total hippocampal volumes. Compared with the HCs, reductions in the left hippocampal subfield volume over the cornu ammonis (CA)1 body, CA2/3 body, CA4 body, granule cell layer, and molecular layer of the dentate gyrus (GC-ML-DG) body, molecular layer of the HP body, and hippocampal tail were more obvious in patients with bvFTD and OCB. Right subfield volumes over the CA1 body and molecular layer of the HP body were more significantly reduced in bvFTD patients with OCB than in those in HCs. We observed no significant difference in amygdalar nuclei volume between the groups. Among patients with bvFTD and OCB, Y-BOCS score was negatively correlated with left CA2/3 body volume (τb = -0.729, p < 0.001); total NPI score was negatively correlated with left GC-ML-DG body (τb = -0.648, p = 0.001) and total bilateral hippocampal volumes (left, τb = -0.629, p = 0.002; right, τb = -0.455, p = 0.023); and FBI score was negatively correlated with the left molecular layer of the HP body (τb = -0.668, p = 0.001), CA4 body (τb = -0.610, p = 0.002), and hippocampal tail volumes (τb = -0.552, p < 0.006). Mediation analysis confirmed these subfield volumes as direct biomarkers for clinical severity, independent of medial and lateral orbitofrontal volumes. (5) Conclusions: Alterations in hippocampal subfield volumes appear to be crucial in the pathophysiology of OCB development in patients with bvFTD.

Revisiting the effects of transcranial direct current stimulation on pattern-reversal visual evoked potentials.

Despite increasing growth of interest in transcranial direct current stimulation (tDCS), its underlying mechanisms are still unclear. With many claims based on the anodal-excitation and cathodal-inhibition dichotomy originally observed in the motor cortex, surprisingly few studies have examined these fundamental polarity-specific effects beyond the motor cortex. The after-effects of tDCS on the visual cortex are of particular interest because of their potential application to vision restoration and migraine treatment. Yet the limited studies revealed conflicting results. Here we investigated whether polarity-specific tDCS effects exist in the visual cortex. In a counterbalanced within-subject crossover design, 20 healthy subjects each completed three sessions of anodal, cathodal and sham tDCS (2 mA for 20 min) applied over the visual cortex. Pattern-reversal visual evoked potentials (VEP) and their habituation slopes were measured at five time-points immediately before, after and every 15 min following the end of tDCS. Compared to sham, we found no significant tDCS induced after-effects on VEP amplitudes or habituation slopes, supported by strong evidence from Bayesian statistics. Neither were there any after-effects of tDCS on EEG power of the frequency of stimulus presentation, theta or alpha band. In conclusion, our results challenge previous findings of robust polarity-dependent after-effects of tDCS over the visual cortex.

Combining Transcranial Direct Current Stimulation With Tai Chi to Improve Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Controlled Trial.

Introduction: Engaging in a secondary task while walking increases motor-cognitive interference and exacerbates fall risk in older adults with mild cognitive impairment (MCI). Previous studies have demonstrated that Tai Chi (TC) may improve cognitive function and dual-task gait performance. Intriguingly, with emerging studies also indicating the potential of transcranial direct current stimulation (tDCS) in enhancing such motor-cognitive performance, whether combining tDCS with TC might be superior to TC alone is still unclear. The purpose of this study was to investigate the effects of combining tDCS with TC on dual-task gait in patients with MCI. Materials and Methods: Twenty patients with MCI were randomly assigned to receive either anodal or sham tDCS, both combined with TC, for 36 sessions over 12 weeks. Subjects received 40 min of TC training in each session. During the first 20 min, they simultaneously received either anodal or sham tDCS over the left dorsolateral prefrontal cortex. Outcome measures included dual-task gait performance and other cognitive functions. Results: There were significant interaction effects between groups on the cognitive dual task walking. Compared to sham, the anodal tDCS group demonstrated a greater improvement on cadence and dual task cost of speed. Conclusion: Combining tDCS with TC may offer additional benefits over TC alone in enhancing dual-task gait performance in patients with MCI. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [TCTR20201201007].

Using Fractal Dimension Analysis with the Desikan-Killiany Atlas to Assess the Effects of Normal Aging on Subregional Cortex Alterations in Adulthood.

Normal aging is associated with functional and structural alterations in the human brain. The effects of normal aging and gender on morphological changes in specific regions of the brain are unknown. The fractal dimension (FD) can be a quantitative measure of cerebral folding. In this study, we used 3D-FD analysis with the Desikan-Killiany (DK) atlas to assess subregional morphological changes in adulthood. A total of 258 participants (112 women and 146 men) aged 30-85 years participated in this study. Participants in the middle-age group exhibited a decreased FD in the lateral frontal lobes, which then spread to the temporal and parietal lobes. Men exhibited an earlier and more significant decrease in FD values, mainly in the right frontal and left parietal lobes. Men exhibited more of a decrease in FD values in the subregions on the left than those in the right, whereas women exhibited more of a decrease in the lateral subregions. Older men were at a higher risk of developing mild cognitive impairment (MCI) and exhibited age-related memory decline earlier than women. Our FD analysis using the DK atlas-based prediagnosis may provide a suitable tool for assessing normal aging and neurodegeneration between groups or in individual patients.

Discontinuation Rate of Newly Prescribed Donepezil in Alzheimer's Disease Patients in Asia.

BACKGROUND AND PURPOSE: The rate of donepezil discontinuation and the underlying reasons for discontinuation in Asian patients with Alzheimer's disease (AD) are currently unknown. We aimed to determine the treatment discontinuation rates in AD patients who had newly been prescribed donepezil in routine clinical practice in Asia. METHODS: This 1-year observational study involved 38 institutions in seven Asian countries, and it evaluated 398 participants aged 50-90 years with a diagnosis of probable AD and on newly prescribed donepezil monotherapy. The primary endpoint was the rate of donepezil discontinuation over 1 year. Secondary endpoints included the reason for discontinuation, treatment duration, changes in cognitive function over the 1-year study period, and compliance as assessed using a clinician rating scale (CRS) and visual analog scale (VAS). RESULTS: Donepezil was discontinued in 83 (20.9%) patients, most commonly due to an adverse event (43.4%). The mean treatment duration was 103.67 days in patients who discontinued. Among patients whose cognitive function was assessed at baseline and 1 year, there were no significant changes in scores on the Mini-Mental State Examination, Montreal Cognitive Assessment, and Trail-Making Test-Black and White scores, whereas the Clinical Dementia Rating score increased significantly (p<0.001). Treatment compliance at 1 year was 96.8% (306/316) on the CRS and 92.6±14.1% (mean±standard deviation) on the VAS. CONCLUSIONS: In patients on newly prescribed donepezil, the primary reason for discontinuation was an adverse event. Cognitive assessments revealed no significant worsening at 1 year, indicating that continuous donepezil treatment contributes to the maintenance of cognitive function.

The visual system as target of non-invasive brain stimulation for migraine treatment: Current insights and future challenges.

The visual network is crucially implicated in the pathophysiology of migraine. Several lines of evidence indicate that migraine is characterized by an altered visual cortex excitability both during and between attacks. Visual symptoms, the most common clinical manifestation of migraine aura, are likely the result of cortical spreading depression originating from the extrastriate area V3A. Photophobia, a clinical hallmark of migraine, is linked to an abnormal sensory processing of the thalamus which is converged with the non-image forming visual pathway. Finally, visual snow is an increasingly recognized persistent visual phenomenon in migraine, possibly caused by increased perception of subthreshold visual stimuli. Emerging research in non-invasive brain stimulation (NIBS) has vastly developed into a diversity of areas with promising potential. One of its clinical applications is the single-pulse transcranial magnetic stimulation (sTMS) applied over the occipital cortex which has been approved for treating migraine with aura, albeit limited evidence. Studies have also investigated other NIBS techniques, such as repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), for migraine prophylaxis but with conflicting results. As a dynamic brain disorder with widespread pathophysiology, targeting migraine with NIBS is challenging. Furthermore, unlike the motor cortex, evidence suggests that the visual cortex may be less plastic. Controversy exists as to whether the same fundamental principles of NIBS, based mainly on findings in the motor cortex, can be applied to the visual cortex. This review aims to explore existing literature surrounding NIBS studies on the visual system of migraine. We will first provide an overview highlighting the direct implication of the visual network in migraine. Next, we will focus on the rationale behind using NIBS for migraine treatment, including its effects on the visual cortex, and the shortcomings of currently available evidence. Finally, we propose a broader perspective of how novel approaches, the concept of brain networks and the integration of multimodal imaging with computational modeling, can help refine current NIBS methods, with the ultimate goal of optimizing a more individualized treatment for migraine.

Clinical and biobehavioral perspectives: Is medication overuse headache a behavior of dependence?

Medication overuse headache (MOH), previously known as analgesic abuse headache or medication misuse headaches, is a common form of chronic headache disorder that has a detrimental impact on health and society. Although it has been widely accepted that overusing abortive medications is paradoxically the cause of MOH and drug discontinuation is the treatment of choice, ongoing debates exist as to whether drug consumption per se is the cause or consequence of headache chronification. Certain features in MOH such as their compulsive drug-seeking behavior, withdrawal headaches and high relapse rates share similarities with drug dependence, suggesting that there might be common underlying biological and psychobehavioral mechanisms. In this regard, this article will discuss the updated evidence and current debates on the possible biobehavioral overlap between MOH and drug dependence. To begin with, we will discuss whether MOH has characteristics of substance dependence based on standard psychiatry diagnostic criteria and other widely used dependence scales. Recent epidemiological studies underscoring common psychiatric comorbidities between the two disorders will also be presented. Although both demonstrate seemingly distinct personality traits, recent studies revealed similar decision-making impairment from a cognitive perspective, indicating the presence of a maladaptive reward system in both disorders. In addition, emerging imaging studies also support this notion by showing reversible morphological and functional brain changes related to the mesocorticolimbic reward circuitry in MOH, with a strong resemblance to those in addiction. Finally, an increased familial risk for drug dependence and genetic association with dopaminergic and drug dependence molecular pathways in MOH also support a possible link between MOH and addiction. Understanding the role of dependence in MOH will have a great impact on disease management as this will provide the missing piece of the puzzle in current therapeutic strategies.

Positive Magnetic Resonance Imaging Evidence of Transient Global Amnesia Following the Use of Sildenafil.

Transient global amnesia (TGA) has been proposed as a possible adverse effect of sildenafil. There are rare cases in the literature, but none had strong evidence to support. Our case is the first to demonstrate a focal punctate diffusion-weighted imaging lesion at the right hippocampus after the use of sildenafil. This finding, which is suggestive of cytotoxic edema and is typical for TGA, may provide us evidence for the implication of sildenafil in TGA. We speculate that sildenafil may precipitate TGA by altering blood flow, inducing venous congestion or cortical spreading depression at the hippocampus.