Brain Connectivity Changes in Postconcussion Syndrome as the Neural Substrate of a Heterogeneous Syndrome.

Background: Postconcussion syndrome (PCS) or persistent symptoms of concussion refers to a constellation of symptoms that persist for weeks and months after a concussion. To better capture the heterogeneity of the symptoms of patients with PCS, we aimed to separate patients into clinical subtypes based on brain connectivity changes. Methods: Subject-specific structural and functional connectomes were created based on diffusion weighted and resting state functional magnetic resonance imaging, respectively. Following an informed dimensionality reduction, a Gaussian mixture model was used on patient-specific structural and functional connectivity matrices to find potential patient clusters. For validation, the resulting patient subtypes were compared in terms of cognitive, neuropsychiatric, and postconcussive symptom differences. Results: Multimodal analyses of brain connectivity were predictive of behavioral outcomes. Our modeling revealed two patient subtypes: mild and severe. The severe subgroup showed significantly higher levels of depression, anxiety, aggression, and a greater number of symptoms than the mild patient subgroup. Conclusion: This study suggests that structural and functional connectivity changes together can help us better understand the symptom severity and neuropsychiatric profiles of patients with PCS. This work allows us to move toward precision medicine in concussions and provides a novel machine learning approach that can be applicable to other heterogeneous conditions.

Cerebrovascular reactivity changes in acute concussion: a controlled cohort study.

BACKGROUND: Evidence suggests that cerebrovascular reactivity (CVR) increases within the first week after the incidence of concussion, indicating a disruption of normal autoregulation. We sought to extend these findings by investigating the effects of acute concussion on the speed of CVR response and by visualizing global and regional impairments in individual patients with acute concussion. METHODS: Twelve patients aged 18-40 years who experienced concussion less than a week before this prospective study were included. Twelve age and sex-matched healthy subjects constituted the control group. In all subjects, CVR was assessed using blood oxygenation level-dependent (BOLD) echo-planar imaging with a 3.0T MRI scanner, in combination with changes in end-tidal partial pressure of CO2 (PETCO2). In each subject, we calculated the CVR amplitude and CVR response time in the gray and white matter using a step and ramp PETCO2 challenge. In addition, a separate group of 39 healthy controls who underwent the same evaluation was used to create atlases with voxel-wise mean and standard deviation of CVR amplitude and CVR response time. This allowed us to convert each metric of the 12 patients with concussion and the 12 healthy controls into z-score maps. These maps were then used to generate and compare z-scores for each of the two groups. Group differences were calculated using an unpaired t-test. RESULTS: All studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study subjects. No differences in CO2 stimulus and O2 targeting were observed between the two participant groups during BOLD MRI. With regard to the gray matter, the CVR magnitude step (P=0.117) and ramp + 10 (P=0.085) were not significantly different between patients with concussion and healthy controls. However, the tau value was significantly lower in patients with concussion than in the healthy controls (P=0.04). With regard to the white matter, the CVR magnitude step (P=0.003) and ramp + 10 (P=0.031) were significantly higher and the tau value (P=0.024) was significantly shorter in patients with concussion than in healthy controls. After z-score transformation, the z tau value was significantly lower in patients with concussion than in healthy controls (Grey matter P=0.021, White matter P=0.003). Comparison of the three parameters, z ramp + 10, z step, and z tau, between the two groups showed that z step (Grey matter P=0.035, White matter P=0.005) was the most sensitive parameter and that z ramp + 10 (Grey matter P=0.073, White matter P=0.126) was the least sensitive parameter. CONCLUSIONS: Concussion is associated with patient-specific abnormalities in BOLD cerebrovascular responsiveness that occur in the setting of normal global CVR. This study demonstrates that the measurement of CVR using BOLD MRI and precise CO2 control is a safe, reliable, reproducible, and clinically useful method for evaluating the state of patients with concussion. It has the potential to be an important tool for assessing the severity and duration of symptoms after concussion.

The Effect of CO2 on Resting-State Functional Connectivity: Isocapnia vs. Poikilocapnia.

The normal variability in breath size and frequency results in breath-to-breath variability of end-tidal PCO2 (PETCO2), the measured variable, and arterial partial pressure of carbon dioxide (PaCO2), the independent variable affecting cerebral blood flow (CBF). This study examines the effect of variability in PaCO2 on the pattern of resting-state functional MRI (rs-fMRI) connectivity. A region of interest (ROI)-to-ROI and Seed-to-Voxel first-level bivariate correlation, hemodynamic response function (hrf)-weighted analysis for measuring rs-fMRI connectivity was performed during two resting-state conditions: (a) normal breathing associated with breath-to-breath variation in PaCO2 (poikilocapnia), and (b) normal breathing with breath-to-breath variability of PETCO2 dampened using sequential rebreathing (isocapnia). End-tidal PCO2 (PETCO2) was used as a measurable surrogate for fluctuations of PaCO2. During poikilocapnia, enhanced functional connections were found between the cerebellum and inferior frontal and supramarginal gyrus (SG), visual cortex and occipital fusiform gyrus; and between the primary visual network (PVN) and the hippocampal formation. During isocapnia, these associations were not seen, rather enhanced functional connections were identified in the corticostriatal pathway between the putamen and intracalacarine cortex, supracalcarine cortex (SCC), and precuneus cortex. We conclude that vascular responses to variations in PETCO2, account for at least some of the observed resting state synchronization of blood oxygenation level-dependent (BOLD) signals.

The value of a shorter-delay arterial spin labeling protocol for detecting cerebrovascular impairment.

BACKGROUND: The aim of this study was to determine the relationship between blood oxygen level dependent (BOLD) cerebrovascular reactivity (CVR) and cerebral blood flow (CBF) obtained from arterial spin labeling (ASL) using different post labeling delays (PLD). METHODS: Forty-two patients with steno-occlusive diseases and impaired CVR were divided into two groups, one scanned with a 1.5-second (1.5-s) and the other with a 2.5-second (2.5-s) PLD ASL protocol. For all patients, a region of interest (ROI) was drawn around the CVR impairment. This affected ROI was then left-right flipped across the brain midline to obtain the control ROI. For both groups, the difference in grey matter CVR between affected and control ROI was first tested to confirm significance. The average grey matter CBF of affected and control ROIs were then compared. The same analysis method was used to compare affected and control hemispheres. RESULTS: In both groups of 1.5-s and 2.5-s PLD, CVR values in the affected ROI (-0.049±0.055 and -0.042±0.074%/mmHg, respectively) were significantly lower compared to that in the control ROI (0.152±0.054 and 0.152±0.053%/mmHg, respectively, P<0.0001). In the group with the 1.5-s PLD, CBF in the affected ROI (37.62±11.37 mL/100 g/min) was significantly lower compared to CBF in the control ROI (44.13±11.58 mL/100 g/min, P<0.05). However, in the group with the 2.5-s PLD, no significant differences could be seen between CBF in the affected ROI (40.50±14.82 mL/100 g/min) and CBF in the control ROI (39.68±12.49 mL/100 g/min, P=0.73). In the hemisphere-based analysis, CBF was significantly lower in the affected side than in the control side for the group with the 1.5-s PLD (P<0.05) when CVR was impaired (P<0.0001), but not for the group with the 2.5-s PLD (P=0.49). CONCLUSIONS: In conclusion, our study reveals and highlights the value of a shorter-PLD ASL protocol, which is able to reflect CVR impairment. At the same time, we offer a better understanding of the relationship between BOLD CVR and CBF obtained from ASL.

Neuroimaging the emotional modulation of urge inhibition in Tourette Syndrome.

Tourette Syndrome (TS) is a neuropsychiatric condition characterized by tics that are typically preceded by uncomfortable urges that build until the tic is performed. Both tics and their associated urges are commonly exacerbated during states of heightened emotion. However, the neural substrates that are responsible for the development of urges have not been fully elucidated, particularly with regards to the influence of emotion. In this study, we investigate the brain areas associated with the development of urges and their modulation by emotion in patients with TS. Moreover, we explore the influence of obsessive-compulsive symptoms (OCS) which are commonly comorbid in TS. Forty patients with TS and 20 healthy controls completed an emotional blink suppression paradigm while undergoing functional magnetic resonance imaging. For the paradigm, participants completed alternating blocks of blink inhibition and free blinking while viewing pictures of angry and neutral facial expressions. Compared to controls, patients exhibited greater activity in the superior temporal gyrus and midcingulate during the inhibition of urges. Within the patient group, tic severity was associated with activity in the superior frontal gyrus during the angry inhibition contrast as compared to neutral; greater premonitory urge severity was associated with greater activity in the hippocampus, middle temporal gyrus and in the subcortex; blink inhibition ability was negatively associated with activity in the thalamus and insula. There were no significant associations with OCS severity for the emotion-related contrasts. The observed activated regions may represent a network that produces urges in patients, or alternatively, could represent compensatory cortical activity needed to keep urges and tics under control during emotional situations. Additionally, our findings suggest that OCS in the context of TS is similar to traditional obsessive-compulsive disorder and is neurobiologically dissociable from tics.

A Promising Subject-Level Classification Model for Acute Concussion Based on Cerebrovascular Reactivity Metrics.

Concussion imaging research has primarily focused on neuronal disruption with lesser emphasis directed toward vascular dysfunction. However, blood flow metrics may be more sensitive than measures of neuronal integrity. Vascular dysfunction can be assessed by measuring cerebrovascular reactivity (CVR)-the change in cerebral blood flow per unit change in vasodilatory stimulus. CVR metrics, including speed and magnitude of flow responses to a standardized well-controlled vasoactive stimulus, are potentially useful for assessing individual subjects following concussion given that blood flow dysregulation is known to occur with traumatic brain injury. We assessed changes in CVR metrics to a standardized vasodilatory stimulus during the acute phase of concussion. Using a case control design, 20 concussed participants and 20 healthy controls (HCs) underwent CVR assessment measuring blood oxygen-level dependent (BOLD) magnetic resonance imaging using precise changes in end-tidal partial pressure of CO2 (PETCO2). Metrics were calculated for the whole brain, gray matter (GM), and white matter (WM) using sex-stratification. A leave-one-out receiver operating characteristic (ROC) analysis classified concussed from HCs based on CVR metrics. CVR magnitude was greater and speed of response faster in concussed participants relative to HCs, with WM showing higher classification accuracy compared with GM. ROC analysis for WM-CVR metrics revealed an area under the curve of 0.94 in males and 0.90 in females for speed and magnitude of response respectively. These greater than normal responses to a vasodilatory stimulus warrant further investigation to compare the predictive ability of CVR metrics against structural injury metrics for diagnosis and prognosis in acute concussion.

Sex-specific differences in resting-state functional connectivity of large-scale networks in postconcussion syndrome.

Concussions are associated with a range of cognitive, neuropsychological and behavioral sequelae that, at times, persist beyond typical recovery times and are referred to as postconcussion syndrome (PCS). There is growing support that concussion can disrupt network-based connectivity post-injury. To date, a significant knowledge gap remains regarding the sex-specific impact of concussion on resting state functional connectivity (rs-FC). The aims of this study were to (1) investigate the injury-based rs-FC differences across three large-scale neural networks and (2) explore the sex-specific impact of injury on network-based connectivity. MRI data was collected from a sample of 80 concussed participants who fulfilled the criteria for postconcussion syndrome and 31 control participants who did not have any history of concussion. Connectivity maps between network nodes and brain regions were used to assess connectivity using the Functional Connectivity (CONN) toolbox. Network based statistics showed that concussed participants were significantly different from healthy controls across both salience and fronto-parietal network nodes. More specifically, distinct subnetwork components were identified in the concussed sample, with hyperconnected frontal nodes and hypoconnected posterior nodes across both the salience and fronto-parietal networks, when compared to the healthy controls. Node-to-region analyses showed sex-specific differences across association cortices, however, driven by distinct networks. Sex-specific network-based alterations in rs-FC post concussion need to be examined to better understand the underlying mechanisms and associations to clinical outcomes.

Accelerated ethanol elimination via the lungs.

Ethanol poisoning is endemic the world over. Morbidity and mortality depend on blood ethanol levels which in turn depend on the balance between its rates of absorption and clearance. Clearance of ethanol is mostly at a constant rate via enzymatic metabolism. We hypothesized that isocapnic hyperpnea (IH), previously shown to be effective in acceleration of clearance of vapour anesthetics and carbon monoxide, would also accelerate the clearance of ethanol. In this proof-of-concept pilot study, five healthy male subjects were brought to a mildly elevated blood ethanol concentration (~ 0.1%) and ethanol clearance monitored during normal ventilation and IH on different days. IH increased elimination rate of ethanol in proportion to blood levels, increasing the elimination rate more than three-fold. Increased veno-arterial ethanol concentration differences during IH verified the efficacy of ethanol clearance via the lung. These data indicate that IH is a nonpharmacologic means to accelerate the elimination of ethanol by superimposing first order elimination kinetics on underlying zero order liver metabolism. Such kinetics may prove useful in treating acute severe ethanol intoxication.

Cerebrovascular Reactivity Assays Collateral Function in Carotid Stenosis.

In patients with carotid artery stenosis (CAS), the risk of stroke, its severity, and response to revascularization are strongly related to the availability of collateral blood flow. Unfortunately, there is poor agreement between observers in assessing collateral flow using flow-based imaging. We used changes in blood-oxygen-level-dependent (BOLD) MRI as a surrogate of changes in regional cerebral blood flow in response to a hypercapnic stimulus [i.e., cerebrovascular reactivity (CVR)] as indicating flow reserve ipsilateral to CAS. We hypothesized that some patients with hemodynamically significant CAS develop functional collateral flow as indicated by normalization of ipsilateral CVR. We identified 55 patients in our CVR database with various degrees of CAS assessed by angiography and classed them as <50% stenosis, 50-69% stenosis, 70-90% stenosis, >90% stenosis, and full occlusion. CVR was measured as the change in BOLD signal in response to changes in end-tidal partial pressure of CO2 (Δ BOLD/Δ PETCO2) and normalized voxel-wise relative to the mean and standard deviation of the CVR in the corresponding voxels of an atlas of 46 healthy controls (CVR z scores). CVR and z scores were then averaged over gray matter (GM) and white matter (WM) on each side of the middle cerebral artery (MCA) territory. As hypothesized, CVR varied for each severity of CAS. Ipsilateral MCA territory CVR was less than normal in each class, including that with <50% stenosis (Student t-test, two-tailed; p = 0.0014 for GM and p = 0.030 for WM), with a trend of decreasing average CVR with increasing stenosis. Remarkably, the considerable individual variability in MCA CVR included some patients with normal CVR in each class - including that with complete occlusion. We conclude that, in general, CAS depresses downstream vascular reserve, but the extent of collateralization is highly variable and not predictable from the degree of stenosis, including both <50% stenosis and complete occlusion. CVR may be the more reliable marker for recruitable collateral blood flow than degree of CAS.

The functional connectivity profile of tics and obsessive-compulsive symptoms in Tourette Syndrome.

Tourette Syndrome (TS) is characterized by the presence of tics and sensory phenomena, such as premonitory urges, and is often accompanied by significant obsessive-compulsive symptoms (OCS). The goal of this exploratory study was to determine the association between functional connectivity and the different symptom domains of TS, as little is currently known about how they differ. Resting-state functional magnetic resonance imaging was performed in 39 patients with TS and 20 matched healthy controls. Seed-based functional connectivity of the supplementary motor area (SMA), orbitofrontal cortex (OFC), insula, caudate and putamen were compared between the groups, and correlated with clinical measures within the patient group. When compared to controls, patients with TS exhibited greater connectivity between the temporal gyri, insula and putamen, and between the OFC and cingulate cortex. Tic severity was associated with greater connectivity between the putamen and the sensorimotor cortex; OCS severity was associated with less connectivity between the SMA and thalamus and between the caudate and precuneus; and premonitory urge severity was associated with less connectivity between the OFC and sensorimotor cortex and between the inferior frontal gyrus and the putamen and insula seeds. Functional connectivity within sensorimotor processing regions were associated with all of the investigated symptom domains, including OCS, suggesting dysfunctions in the sensorimotor system may explain most of the observed symptoms in TS, and not just tics.

Slowed Temporal and Parietal Cerebrovascular Response in Patients with Alzheimer's Disease.

BACKGROUND: Recent investigations now suggest that cerebrovascular reactivity (CVR) is impaired in Alzheimer's disease (AD) and may underpin part of the disease's neurovascular component. However, our understanding of the relationship between the magnitude of CVR, the speed of cerebrovascular response, and the progression of AD is still limited. This is especially true in patients with mild cognitive impairment (MCI), which is recognized as an intermediate stage between normal aging and dementia. The purpose of this study was to investigate AD and MCI patients by mapping repeatable and accurate measures of cerebrovascular function, namely the magnitude and speed of cerebrovascular response (τ) to a vasoactive stimulus in key predilection sites for vascular dysfunction in AD. METHODS: Thirty-three subjects (age range: 52-83 years, 20 males) were prospectively recruited. CVR and τ were assessed using blood oxygen level-dependent MRI during a standardized carbon dioxide stimulus. Temporal and parietal cortical regions of interest (ROIs) were generated from anatomical images using the FreeSurfer image analysis suite. RESULTS: Of 33 subjects recruited, 3 individuals were excluded, leaving 30 subjects for analysis, consisting of 6 individuals with early AD, 11 individuals with MCI, and 13 older healthy controls (HCs). τ was found to be significantly higher in the AD group compared to the HC group in both the temporal (p = 0.03) and parietal cortex (p = 0.01) following a one-way ANCOVA correcting for age and microangiopathy scoring and a Bonferroni post-hoc correction. CONCLUSION: The study findings suggest that AD is associated with a slowing of the cerebrovascular response in the temporal and parietal cortices.

Examining the functional activity of different obsessive-compulsive symptom dimensions in Tourette syndrome.

OBJECTIVES: Tourette syndrome (TS) is commonly comorbid with obsessive-compulsive disorder (OCD) and many phenomenological similarities exist between tics and obsessive-compulsive symptoms (OCS). Therefore, due to the clinical importance of comorbid OCD, the goal of this study was to investigate the neural substrates of OCS in TS using functional magnetic resonance imaging. METHODS: Forty patients with TS and 20 healthy controls underwent functional magnetic resonance imaging while viewing blocks of OCS-provoking pictures relating to washing, checking and symmetry symptoms, as well as generally disgusting and neutral scenes. Statistical comparisons were made between patients with moderate/severe OCS, absent/mild OCS and healthy controls. As well, within the entire TS patient group, significant associations with clinical measures were assessed for each of the provocation conditions. RESULTS: Group differences in the insula, sensorimotor cortex, supramarginal gyrus and visual processing regions were common among the checking, washing and disgust conditions. In the patient group, negative associations between OCS severity and activity in the supramarginal gyrus, inferior frontal gyrus, sensorimotor cortex, precuneus and visual processing regions were common among the provocation conditions. Tic severity was only associated with activity in the anterior cingulate cortex for the symmetry condition. CONCLUSION: Our findings implicate areas previously reported to be involved in OCD, as well as areas not typically implicated in OCD, suggesting that the neurobiological profile of TS+OCD is intermediate to pure TS and pure OCD.

The efficiency of the brain connectome is associated with cerebrovascular reactivity in persons with white matter hyperintensities.

The purpose of this study was to determine the relationship between the organization of the brain connectome and cerebrovascular reactivity (CVR) in persons with white matter hyperintensities. Diffusion tensor and CVR mapping 3T MRI scans were acquired in 31 participants with white matter hyperintensities. In each participant, the connectome was assessed by reconstructing all white matter tracts with tractography and segmenting the whole brain into multiple regions. Graph theory analysis was performed to quantify how effectively tracts connected brain regions by measuring the global and local efficiency of the connectome. CVR in white matter and gray matter was correlated with the global and local efficiency of the connectome, while adjusting for age, gender, and gray matter volume. For comparison, white matter hyperintensity volume was also correlated with global and local efficiency. White matter CVR was positively correlated with the global efficiency (coefficient: 23.3, p = .005) and local efficiency (coefficient: 2850, p = .004) of the connectome. Gray matter CVR was positively correlated with the global efficiency (coefficient: 21.3, p < .001) and local efficiency (coefficient: 2670, p < .001) of the connectome. White matter hyperintensity volume was negatively correlated with global efficiency (coefficient: -0.0002, p = .003) and local efficiency (coefficient: -0.024, p = .003) of the connectome. The association between CVR and the brain connectome suggests that impaired cerebrovascular function may be part of the pathophysiology of the disruption of the brain connectome in persons with white matter hyperintensities.

Cerebrovascular Resistance in Healthy Aging and Mild Cognitive Impairment.

Measures of cerebrovascular reactivity (CVR) are used to judge the health of the brain vasculature. In this study, we report the use of several different analyses of blood oxygen dependent (BOLD) fMRI responses to CO2 to provide a number of metrics of CVR based on the sigmoidal resistance response to CO2. To assess possible differences in these metrics with age, we compiled atlases reflecting voxel-wise means and standard deviations for four different age ranges and for a group of patients with mild cognitive impairment (MCI) and compared them. Sixty-seven subjects were recruited for this study and scanned at 3T field strength. Of those, 51 healthy control volunteers between the ages of 18-83 were recruited, and 16 (MCI) subjects between the ages of 61-83 were recruited. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm while monitoring end-tidal partial pressures of CO2. Surprisingly, some resistance sigmoid parameters in the oldest control group were increased compared to the youngest control group. Resistance amplitude maps showed increases in clusters within the temporal cortex, thalamus, corpus callosum and brainstem, and resistance reserve maps showed increases in clusters within the cingulate cortex, frontal gyrus, and corpus callosum. These findings suggest that some aspects of vascular reactivity in parts of the brain are initially maintained with age but then may increase in later years. We found significant reductions in all resistance sigmoid parameters (amplitude, reserve, sensitivity, midpoint, and range) when comparing MCI patients to controls. Additionally, in controls and in MCI patients, amplitude, range, reserve, and sensitivity in white matter (WM) was significantly reduced compared to gray matter (GM). WM midpoints were significantly above those of GM. Our general conclusion is that vascular regulation in terms of cerebral blood flow (CBF) responsiveness to CO2 is not significantly affected by age, but is reduced in MCI. These changes in cerebrovascular regulation demonstrate the value of resistance metrics for mapping areas of dysregulated blood flow in individuals with MCI. They may also be of value in the investigation of patients with vascular risk factors at risk for developing vascular dementia.

3-Tesla MRI of deep brain stimulation patients: safety assessment of coils and pulse sequences.

OBJECTIVE: Physicians are more frequently encountering patients who are treated with deep brain stimulation (DBS), yet many MRI centers do not routinely perform MRI in this population. This warrants a safety assessment to improve DBS patients' accessibility to MRI, thereby improving their care while simultaneously providing a new tool for neuromodulation research. METHODS: A phantom simulating a patient with a DBS neuromodulation device (DBS lead model 3387 and IPG Activa PC model 37601) was constructed and used. Temperature changes at the most ventral DBS electrode contacts, implantable pulse generator (IPG) voltages, specific absorption rate (SAR), and B1+rms were recorded during 3-T MRI scanning. Safety data were acquired with a transmit body multi-array receive and quadrature transmit-receive head coil during various pulse sequences, using numerous DBS configurations from "the worst" to "the most common."In addition, 3-T MRI scanning (T1 and fMRI) was performed on 41 patients with fully internalized and active DBS using a quadrature transmit-receive head coil. MR images, neurological examination findings, and stability of the IPG impedances were assessed. RESULTS: In the phantom study, temperature rises at the DBS electrodes were less than 2°C for both coils during 3D SPGR, EPI, DTI, and SWI. Sequences with intense radiofrequency pulses such as T2-weighted sequences may cause higher heating (due to their higher SAR). The IPG did not power off and kept a constant firing rate, and its average voltage output was unchanged. The 41 DBS patients underwent 3-T MRI with no adverse event. CONCLUSIONS: Under the experimental conditions used in this study, 3-T MRI scanning of DBS patients with selected pulse sequences appears to be safe. Generally, T2-weighted sequences (using routine protocols) should be avoided in DBS patients. Complementary 3-T MRI phantom safety data suggest that imaging conditions that are less restrictive than those used in the patients in this study, such as using transmit body multi-array receive coils, may also be safe. Given the interplay between the implanted DBS neuromodulation device and the MRI system, these findings are specific to the experimental conditions in this study.

A mechanistic cohort study evaluating cognitive impairment in women treated for breast cancer.

Some women report cognitive impairment after adjuvant chemotherapy (CTh) for breast cancer. Here we explore cognitive function, and underlying mechanisms with blood tests and functional magnetic resonance imaging (fMRI). Women treated for early breast cancer were recruited to three groups based on self-reported cognitive symptoms (CS) using FACT-Cog scores. CTh + CS+ (n = 44) had received chemotherapy and self-reported cognitive symptoms; CTh + CS- (n = 52) had chemotherapy but did not report cognitive problems; CTh- (n = 30) had not received chemotherapy. Clinical and computer-based neuropsychological tests were performed. Blood tests included 10 cytokines, sex hormones, coagulation factors, and apolipoprotein-E genotype. fMRI (n = 101) was performed while subjects performed an n-back memory task. Participants had median age 50 (range: 29-60) years and were a median of 17 months post-diagnosis. On clinical neuropsychological tests 19% had cognitive impairment using Global Deficit Score, and 36% using International Cancer and Cognition Task Force criteria with no significant differences in cognitive impairment rates between groups. CTh + CS+ had significantly more fatigue, anxiety/depression and poorer quality-of-life than other groups. There was no association between FACT-Cog and neuropsychological scores. There were significant differences in frontal and parietal regions on fMRI scans: CTh- showed hyperactivation compared to chemotherapy-treated groups, CTh + CS+ had more frontal activation than CTh + CS-. Elevated IL-1, IL-2 were associated weakly and IL-8 more strongly with neuropsychological impairment (rho > 0.20). There were no differences in global cognitive impairment between groups. Cognitive symptoms were associated with fatigue and anxiety/depression, but not with objective cognitive impairment. fMRI scans differed among the three groups.

Neuropathic pain and pain interference are linked to alpha-band slowing and reduced beta-band magnetoencephalography activity within the dynamic pain connectome in patients with multiple sclerosis.

Chronic pain is a common occurrence in multiple sclerosis (MS) that severely affects quality of life, but the underlying brain mechanisms related to these symptoms are unknown. Previous electroencephalography studies have demonstrated a role of alpha-band and beta-band power in pain processing. However, how and where these brain signals change in MS-related chronic pain is unknown. Here, we used resting state magnetoencephalography to examine regional spectral power in the dynamic pain connectome-including areas of the ascending nociceptive pathway, default mode network (DMN), and the salience network (SN)-in patients with chronic MS pain and in healthy controls. Each patient was assessed for pain, neuropathic pain (NP), and pain interference with activities of daily living. We found that patients with MS exhibited an increase of alpha-band power and a decrease of beta-band power, most prominently in the thalamus and the posterior insula of the ascending nociceptive pathway and in the right temporoparietal junction of the SN. In addition, patients with mixed-NP exhibited slowing of alpha peak power within the thalamus and the posterior insula, and in the posterior cingulate cortex of the DMN. Finally, pain interference scores in patients with mixed-NP were strongly correlated with alpha and beta peak power in the thalamus and posterior insula. These novel findings reveal brain mechanisms of MS-related pain in the ascending nociceptive pathway, SN, and DMN, and that these spectral abnormalities reflect the impact of pain on quality of life measures.

Correction: Monitoring for myelopathic progression with multiparametric quantitative MRI.

[This corrects the article DOI: 10.1371/journal.pone.0195733.].

Cerebrovascular Resistance: The Basis of Cerebrovascular Reactivity.

The cerebral vascular network regulates blood flow distribution by adjusting vessel diameters, and consequently resistance to flow, in response to metabolic demands (neurovascular coupling) and changes in perfusion pressure (autoregulation). Deliberate changes in carbon dioxide (CO2) partial pressure may be used to challenge this regulation and assess its performance since CO2 also acts to change vessel diameter. Cerebrovascular reactivity (CVR), the ratio of cerebral blood flow (CBF) response to CO2 stimulus is currently used as a performance metric. However, the ability of CVR to reflect the responsiveness of a particular vascular region is confounded by that region's inclusion in the cerebral vascular network, where all regions respond to the global CO2 stimulus. Consequently, local CBF responses reflect not only changes in the local vascular resistance but also the effect of changes in local perfusion pressure resulting from redistribution of flow within the network. As a result, the CBF responses to CO2 take on various non-linear patterns that are not well-described by straight lines. We propose a method using a simple model to convert these CBF response patterns to the pattern of resistance responses that underlie them. The model, which has been used previously to explain the steal phenomenon, consists of two vascular branches in parallel fed by a major artery with a fixed resistance unchanging with CO2. One branch has a reference resistance with a sigmoidal response to CO2, representative of a voxel with a robust response. The other branch has a CBF equal to the measured CBF response to CO2 of any voxel under examination. Using the model to calculate resistance response patterns of the examined branch showed sigmoidal patterns of resistance response, regardless of the measured CBF response patterns. The sigmoid parameters of the resistance response pattern of examined voxels may be mapped to their anatomical location. We show an example for a healthy subject and for a patient with steno-occlusive disease to illustrate. We suggest that these maps provide physiological insight into the regulation of CBF distribution.

Impact of white matter hyperintensities on surrounding white matter tracts.

PURPOSE: It is unclear how white matter hyperintensities disrupt surrounding white matter tracts. The aim of this tractography study was to determine the spatial relationship between diffusion characteristics along white matter tracts and the distance from white matter hyperintensities. METHODS: Diffusion tensor 3-T MRI scans were acquired in 29 participants with white matter hyperintensities. In each subject, tractography by the fiber assignment by continuous tracking method was used to segment corticospinal tracts. Mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy were measured along corticospinal tracts in relation to white matter hyperintensities. Diffusion characteristics along tracts were correlated with distance from white matter hyperintensities and were also compared between tracts traversing and not traversing white matter hyperintensities. RESULTS: In tracts not traversing through white matter hyperintensities, increasing distance from white matter hyperintensities was associated with decreased mean diffusivity (p = 0.002) and increased fractional anisotropy (p = 0.006). In tracts traversing white matter hyperintensities, compared to tracts not traversing white matter hyperintensites, the mean diffusivity was higher at 6-8 voxels, axial diffusivity higher at 4-8 voxels, and radial diffusivity higher at 7 voxels away from white matter hyperintensities (all p < 0.006). CONCLUSION: White matter hyperintensities are associated with two patterns of altered diffusion characteristics in the surrounding white matter tract network. Diffusion characteristics along white matter tracts improve further away from white matter hyperintensities suggestive of a local penumbra pattern. Also, altered diffusion extends further along tracts traversing white matter hyperintensities suggestive of a Wallerian-type degenerative pattern.