Migraine Management in Medically Complex Patients: a Narrative Review.

PURPOSE OF REVIEW: The current review aims to provide an overview of migraine treatment strategies in medically complex patients, including those with renal, liver, and cardiovascular disease. RECENT FINDINGS: In cardiovascular disease, gepants are likely safe for acute therapy; NSAIDs, ergotamines, and triptans are not recommended. Beta-blockers, ACEi/ARBs, and verapamil have potential cardiovascular benefits in addition to migraine preventive benefit. Frovatriptan requires no dose adjustments in kidney disease or in mild to moderate liver disease. Gepants are safe acute and preventive treatment options in mild and moderate renal and hepatic disease. TCAs and valproic acid require no dose adjustments in renal disease. OnabotulinumtoxinA is likely safe in cardiac, renal, and hepatic impairment. Although CGRP monoclonal antibodies are likely safe in renal and hepatic disease, further study is needed in these conditions as well as in cardiac disease, and no dosing recommendations are available. Effective options are available for those with complex medical comorbidities. Further research is required on the safety of newer migraine-specific therapies in these complex populations.

Resting-state functional connectivity indicators of risk and resilience for self-harm in adolescent bipolar disorder.

BACKGROUND: Suicide is the second leading cause of death in all youth and among adults with bipolar disorder (BD). The risk of suicide in BD is among the highest of all psychiatric conditions. Self-harm, including suicide attempts and non-suicidal self-injury, is a leading risk factor for suicide. Neuroimaging studies suggest reward circuits are implicated in both BD and self-harm; however, studies have yet to examine self-harm related resting-state functional connectivity (rsFC) phenotypes within adolescent BD. METHODS: Resting-state fMRI data were analyzed for 141 adolescents, ages 13-20 years, including 38 with BD and lifetime self-harm (BDSH+), 33 with BD and no self-harm (BDSH-), and 70 healthy controls (HC). The dorsolateral prefrontal cortex (dlPFC), orbitofrontal cortex (OFC) and amygdala were examined as regions of interest in seed-to-voxel analyses. A general linear model was used to explore the bivariate correlations for each seed. RESULTS: BDSH- had increased positive rsFC between the left amygdala and left lateral occipital cortex, and between the right dlPFC and right frontal pole, and increased negative rsFC between the left amygdala and left superior frontal gyrus compared to BDSH+ and HC. BDSH+ had increased positive rsFC of the right OFC with the precuneus and left paracingulate gyrus compared to BDSH- and HC. CONCLUSIONS: This study provides preliminary evidence of altered reward-related rsFC in relation to self-harm in adolescents with BD. Between-group differences conveyed a combination of putative risk and resilience connectivity patterns. Future studies are warranted to evaluate changes in rsFC in response to treatment and related changes in self-harm.

Medication Overuse Headache: an Updated Review and Clinical Recommendations on Management.

OVERVIEW: Medication overuse headache (MOH) is highly prevalent among individuals with primary headache disorders. PURPOSE OF REVIEW: (1) Provide an update on epidemiology, risk factors, and treatment strategies of MOH and (2) provide recommendations on the management of MOH. RECENT FINDINGS: The prevalence of MOH ranges from 0.5 to 7.2%. Risk factors for MOH include female sex, lower socioeconomic status, some psychiatric conditions, and substance use disorders, among others. Recent large clinical trials support preventative therapy as an integral component of MOH management. Emerging clinical trial evidence supports anti-CGRP mAbs as effective preventative treatments among individuals with migraine and MOH. Among the large clinical trials, candesartan, topiramate, amitriptyline, and onabotulinumtoxinA were the most used preventative therapies, providing further support for these agents. MOH management requires a multifaceted and patient-centered approach that involves patient education, behavioral interventions, withdrawal of the overused medication, and initiation of preventative medication.

Cannabis use and resting state functional connectivity in adolescent bipolar disorder.

BACKGROUND: Adolescents with bipolar disorder have high rates of cannabis use, and cannabis use is associated with increased symptom severity and treatment resistance in bipolar disorder. Studies have identified anomalous resting-state functional connectivity among reward networks in bipolar disorder and cannabis use independently, but have yet to examine their convergence. METHODS: Participants included 134 adolescents, aged 13 to 20 years: 40 with bipolar disorder and lifetime cannabis use, 31 with bipolar disorder and no history of cannabis use, and 63 healthy controls without lifetime cannabis use. We used a seed-to-voxel analysis to assess the restingstate functional connectivity of the amygdala, the nucleus accumbens and the orbitofrontal cortex, regions implicated in bipolar disorder and cannabis use. We used a generalized linear model to explore bivariate correlations for each seed, controlling for age and sex. RESULTS: We found 3 significant clusters. Resting-state functional connectivity between the left nucleus accumbens seed and the left superior parietal lobe was negative in adolescents with bipolar disorder and no history of cannabis use, and positive in healthy controls. Resting-state functional connectivity between the right orbitofrontal cortex seed and the right lateral occipital cortex was positive in adolescents with bipolar disorder and lifetime cannabis use, and negative in healthy controls and adolescents with bipolar disorder and no history of cannabis use. Resting-state functional connectivity between the right orbitofrontal cortex seed and right occipital pole was positive in adolescents with bipolar disorder and lifetime cannabis use, and negative in adolescents with bipolar disorder and no history of cannabis use. LIMITATIONS: The study did not include a cannabis-using control group. CONCLUSION: This study provides preliminary evidence of cannabis-related differences in functional reward circuits in adolescents with bipolar disorder. Further studies are necessary to evaluate whether the present findings reflect consequences of or predisposition to cannabis use.

Cognitive, on-road, and simulator-based driving assessment after stroke.

Driving is a complex activity that requires intact cognitive, behavioral, and motor function. Stroke is one of the most prevalent neurologic impairments and can affect all of these functions. However, diagnosis of stroke is not a definitive indicator of driving impairment. Determining fitness to drive after stroke is a very complex process and is typically based on cognitive assessments, on-road performance, simulator-based assessment, or a combination of the three. The aim of this review was to provide (1) a systematic review of the literature on cognitive, on-road, and simulator assessment after stroke, and (2) address the existing limitations and inconsistencies in stroke and driving research. Our results indicated that of 1413 total stroke patients, 748 definitively passed and 367 definitely failed an on-road assessment, with minimal information provided about clinical presentation. In addition, although the Stroke Driver Screening Assessment, the Useful Field of View Test, and the Rey-O Complex Figure test may have some utility in predicting driving performance, most cognitive measures have been inconsistently and minimally explored. Several limitations were observed across studies such as procedural inconsistencies, including outcome variables used (eg, driving cessation and pass/fail classification) and the heterogeneity of patient samples (eg, time since stroke and stroke location). Due, in part, to the larger variability in results of cognitive, on-road, and simulator-based assessment, there is no consensus regarding a valid and reliable driving assessment for physicians. Future studies should assess poststroke driving fitness by differentiating different stages, severities, and locations of stroke.

Severe anhedonia among adolescents with bipolar disorder is common and associated with increased psychiatric symptom burden.

BACKGROUND: Anhedonia, a deficit in the ability to experience pleasure, is a cardinal symptom of major depressive episodes. In contrast to adolescent major depressive disorder, there is limited research examining anhedonia in the context of depression among adolescents with bipolar disorder (BD). We therefore examined clinical characteristics of anhedonia in a large sample of adolescents with BD. METHODS: Participants were 197 adolescents, aged 13-20 years old, with BD type I, II or not otherwise specified. Diagnoses were determined using a semi-structured interview. Anhedonia severity was rated from one to six on the Depression Rating Scale (DRS). Adolescents were divided into "severe" and "non-severe" anhedonia groups based on the DRS item scoring. The association of anhedonia with clinical and demographic variables was evaluated in univariate analyses followed by logistic regression analyses for variables with p ≤ 0.1. RESULTS: Threshold anhedonia was evident among 90.9% during their most severe depressive episode. Significant factors associated with severe most severe lifetime anhedonia ("lifetime anhedonia") included: female sex, lifetime history of self-injurious behavior, physical abuse, affective lability, higher lifetime depression severity, comorbid anxiety disorders, family history of ADHD, and second-generation antipsychotic use. In regression analyses, severe lifetime anhedonia was independently associated with female sex, comorbid anxiety disorders, most severe lifetime mania severity, and lifetime second-generation antipsychotic use. CONCLUSION: The vast majority of adolescents with BD experience anhedonia. More severe anhedonia is associated with indicators of greater illness severity. Future research is warranted to evaluate the neurobiological underpinnings of anhedonia among adolescents with BD.

Functional magnetic resonance imaging of the trail-making test in older adults.

The trail-making test (TMT) is a popular neuropsychological test, which is used extensively to measure cognitive impairment associated with neurodegenerative disorders in older adults. Behavioural performance on the TMT has been investigated in older populations, but there is limited research on task-related brain activity in older adults. The current study administered a naturalistic version of the TMT to a healthy older-aged population in an MRI environment using a novel, MRI-compatible tablet. Functional MRI was conducted during task completion, allowing characterization of the brain activity associated with the TMT. Performance on the TMT was evaluated using number of errors and seconds per completion of each link. Results are reported for 36 cognitively healthy older adults between the ages of 52 and 85. Task-related activation was observed in extensive regions of the bilateral frontal, parietal, temporal and occipital lobes as well as key motor areas. Increased age was associated with reduced brain activity and worse task performance. Specifically, older age was correlated with decreased task-related activity in the bilateral occipital, temporal and parietal lobes. These results suggest that healthy older aging significantly affects brain function during the TMT, which consequently may result in performance decrements. The current study reveals the brain activation patterns underlying TMT performance in a healthy older aging population, which functions as an important, clinically-relevant control to compare to pathological aging in future investigations.

The Neural Correlates of the Clock-Drawing Test in Healthy Aging.

Importance: The clock-drawing test (CDT) is an important neurocognitive assessment tool, widely used as a screening test for dementia. Behavioral performance on the test has been studied extensively, but there is scant literature on the underlying neural correlates. Purpose: To administer the CDT naturalistically to a healthy older aging population in an MRI environment, and characterize the brain activity associated with test completion. Main Outcome and Measure: Blood-oxygen-level dependent (BOLD) functional MRI was conducted as participants completed the CDT using novel tablet technology. Brain activity during CDT performance was contrasted to rest periods of visual fixation. Performance on the CDT was evaluated using a standardized scoring system (Rouleau score) and time to test completion. To assess convergent validity, performance during fMRI was compared to performance on a standard paper version of the task, administered in a psychometric testing room. Results: Study findings are reported for 33 cognitively healthy older participants aged 52-85. Activation was observed in the bilateral frontal, occipital and parietal lobes as well as the supplementary motor area and precentral gyri. Increased age was significantly correlated with Rouleau scores on the clock number drawing (R2) component (rho = -0.55, p < 0.001); the clock hand drawing (R3) component (rho = -0.50, p < 0.005); and the total clock (rho = -0.62, p < 0.001). Increased age was also associated with decreased activity in the bilateral parietal and occipital lobes as well as the right temporal lobe and right motor areas. Conclusion and Relevance: This imaging study characterizes the brain activity underlying performance of the CDT in a healthy older aging population using the most naturalistic version of the task to date. The results suggest that the functions of the occipital and parietal lobe are significantly altered by the normal aging process, which may lead to performance decrements.

A Case-Control Study Investigating Simulated Driving Errors in Ischemic Stroke and Subarachnoid Hemorrhage.

BACKGROUND: Stroke can affect a variety of cognitive, perceptual, and motor abilities that are important for safe driving. Results of studies assessing post-stroke driving ability are quite variable in the areas and degree of driving impairment among patients. This highlights the need to consider clinical characteristics, including stroke subtype, when assessing driving performance. METHODS: We compared the simulated driving performance of 30 chronic stroke patients (>3 months), including 15 patients with ischemic stroke (IS) and 15 patients with subarachnoid hemorrhage (SAH), and 20 age-matched controls. A preliminary analysis was performed, subdividing IS patients into right (n = 8) and left (n = 6) hemispheric lesions and SAH patients into middle cerebral artery (MCA, n = 5) and anterior communicating artery (n = 6) territory. A secondary analysis was conducted to investigate the cognitive correlates of driving. RESULTS: Nine patients (30%) exhibited impaired simulated driving performance, including four patients with IS (26.7%) and five patients with SAH (33.3%). Both patients with IS (2.3 vs. 0.3, U = 76, p < 0.05) and SAH (1.5 vs. 0.3, U = 45, p < 0.001) exhibited difficulty with lane maintenance (% distance out of lane) compared to controls. In addition, patients with IS exhibited difficulty with speed maintenance (% distance over speed limit; 8.9 vs. 4.1, U = 81, p < 0.05), whereas SAH patients exhibited difficulty with turning performance (total turning errors; 5.4 vs. 1.6, U = 39.5, p < 0.001). The Trail Making Test (TMT) and Useful Field of View test were significantly associated with lane maintenance among patients with IS (rs > 0.6, p < 0.05). No cognitive tests showed utility among patients with SAH. CONCLUSION: Both IS and SAH exhibited difficulty with lane maintenance. Patients with IS additionally exhibited difficulty with speed maintenance, whereas SAH patients exhibited difficulty with turning performance. Current results support the importance of differentiating between stroke subtypes and considering other important clinical characteristics (e.g., side of lesion, vascular territory) when assessing driving performance and reinforce the importance of physicians discussing driving safety with patients after stroke.

Driving habits and behaviors of patients with brain tumors: a self-report, cognitive and driving simulation study.

The purpose of the study is to determine driving habits and behaviors of patients with brain tumors in order to better inform discussions around driving safety in this population. Eight-four patients with brain tumors participated in a survey on their driving behaviors since their diagnosis. Thirteen of these patients and thirteen sex- and age-matched healthy controls participated in cognitive testing and several driving simulation scenarios in order to objectively assess driving performance. Survey responses demonstrated that patients with brain tumors engage in a variety of driving scenarios with little subjectve difficulty. On the driving simulation tasks, patients and healthy controls performed similarly except that patients had more speed exceedances (U = 41, p < 0.05) and a greater variability in speed (U = 57, p < 0.05). Performance on the selective attention component of the UFOV was significantly associated with greater total errors in the Bus Following task for patients with brain tumors compared to healthy controls (rs = 0.722, p < 0.05, CI [0.080, 0.957]). Better comprehensive driving assessments are needed to identify patients with driving behaviors that put themselves and others at risk on the road.

Altered Functional Brain Connectivity in Mild Cognitive Impairment during a Cognitively Complex Car Following Task.

Mild cognitive impairment (MCI) can affect multiple cognitive abilities, leading to difficulty in performing complex, cognitively demanding daily tasks, such as driving. This study combined driving simulation and functional magnetic resonance imaging (fMRI) to investigate brain function in individuals with MCI while they performed a car-following task. The behavioral driving performance of 24 patients with MCI and 20 healthy age-matched controls was compared during a simulated car-following task. Functional brain connectivity during driving was analyzed for a separate cohort of 15 patients with MCI and 15 controls. Individuals with MCI had minor difficulty with lane maintenance, exhibiting significantly increased variability in steering compared to controls. Patients with MCI also exhibited reduced connectivity between fronto-parietal regions, as well as between regions involved in cognitive control (medial frontal cortex) and regions important for visual processing (cuneus, angular gyrus, superior occipital cortex, inferior and superior parietal cortex). Greater difficulty in lane maintenance (i.e., increased steering variability and lane deviations) among individuals with MCI was further associated with increased connectivity between the posterior cingulate cortex (PCC) and inferior frontal gyrus, as well as increased intra-cerebellar connectivity. Thus, compared to cognitively healthy controls, patients with MCI showed reduced connectivity between regions involved in visual attention, visual processing, cognitive control, and performance monitoring. Greater difficulty with lane maintenance among patients with MCI may reflect failure to inhibit components of the default-mode network (PCC), leading to interference with task-relevant networks as well as alterations in cerebellum connectivity.

Investigating Simulated Driving Errors in Amnestic Single- and Multiple-Domain Mild Cognitive Impairment.

The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n = 11) and amnestic multiple-domain MCI (md-MCI, n = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when evaluating driving safety.

A Systematic Review and Meta-Analysis of On-Road Simulator and Cognitive Driving Assessment in Alzheimer's Disease and Mild Cognitive Impairment.

BACKGROUND: Many individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) are at an increased risk of driving impairment. There is a need for tools with sufficient validity to help clinicians assess driving ability. OBJECTIVE: Provide a systematic review and meta-analysis of the primary driving assessment methods (on-road, cognitive, driving simulation assessments) in patients with MCI and AD. METHODS: We investigated (1) the predictive utility of cognitive tests and domains, and (2) the areas and degree of driving impairment in patients with MCI and AD. Effect sizes were derived and analyzed in a random effects model. RESULTS: Thirty-two articles (including 1,293 AD patients, 92 MCI patients, 2,040 healthy older controls) met inclusion criteria. Driving outcomes included: On-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior. Executive function (ES [95% CI]; 0.61 [0.41, 0.81]), attention (0.55 [0.33, 0.77]), visuospatial function (0.50 [0.34, 0.65]), and global cognition (0.61 [0.39, 0.83]) emerged as significant predictors of driving performance. Trail Making Test Part B (TMT-B, 0.61 [0.28, 0.94]), TMT-A (0.65 [0.08, 1.21]), and Maze test (0.88 [0.60, 1.15]) emerged as the best single predictors of driving performance. Patients with very mild AD (CDR = 0.5) mild AD (CDR = 1) were more likely to fail an on-road test than healthy control drivers (CDR = 0), with failure rates of 13.6%, 33.3% and 1.6%, respectively. CONCLUSION: The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients. Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and MCI (amnestic, non-amnestic, single-domain, multiple-domain).

Is it safe to drive after acute mild stroke? A preliminary report.

BACKGROUND: Most guidelines recommend that patients should refrain from driving for at least one month after stroke. Despite these guidelines, and the fact that patients post-stroke may be at an increased risk for driving impairment, many patients report resuming driving within the acute phase of injury. The aim of this study was to investigate the driving performance of patients with acute mild stroke. METHODS: The current study compared the driving simulator performance of ten patients with acute mild ischemic stroke (>48 h and <7 days) to that of ten healthy, age- and education-matched controls. RESULTS: During the City Driving and Bus Following Scenarios, patients on average committed over twice as many errors (e.g., collisions, center line crossings, speed exceedances) as controls (12.4 vs. 6.0, t(18)=2.77, p<0.01; and 8.2 vs. 2.1, t(17)=2.55, p<0.05; respectively). Although there was no difference between patients and controls in the number of errors committed during simple right and left turns, patients committed significantly more errors than controls during left turns with traffic (0.49 vs. 0.26, U=26.5, p<0.05). CONCLUSION: Results suggest that patients with acute mild ischemic stroke may be able to maintain driving performance during basic tasks (e.g., straight driving, right turns) and that deficits may become apparent during more complex tasks (e.g., left turns with traffic, bus following). The results highlight the importance of healthcare professionals providing driving advice to their patients post-stroke, particularly in the acute phase of injury.

Using fMRI virtual-reality technology to predict driving ability after brain damage: a preliminary report.

The cerebellum, which is important for movement control and planning, is often affected by many neurological conditions. Until now there has been limited information regarding how the function of the cerebellum impacts driving ability. This study used fMRI with an integrated virtual reality driving simulator to determine which aspects of driving performance are related to the cerebellum in healthy drivers (Experiment 1). It also investigated drivers with focal cerebellar lesions to identify how damage to this brain region impairs driving abilities. The results showed that cerebellar functioning is responsible for motor-speed coordination and complex temporal-motor integration necessary to execute driving behaviours. As predicted, drivers with cerebellar damage, showed significantly compromised speed control during basic driving conditions, whereas their ability to perform during interactive driving situations was preserved. New insights into neural mechanisms and brain plasticity regarding driving behaviour are discussed. Strategies in assessing and rehabilitating drivers with related neurological conditions are provided.