Cognitive impairment after focal brain lesions is better predicted by damage to structural than functional network hubs

Hubs are highly connected brain regions important for coordinating processing in brain networks. It is unclear, however, which measures of network “hubness” are most useful in identifying brain regions critical to human cognition. We tested how closely two measures of hubness—edge density and participation coefficient, derived from white and gray matter, respectively—were associated with general cognitive impairment after brain damage in two large cohorts of patients with focal brain lesions (N = 402 and 102, respectively) using cognitive tests spanning multiple cognitive domains. Lesions disrupting white matter regions with high edge density were associated with cognitive impairment, whereas lesions damaging gray matter regions with high participation coefficient had a weaker, less consistent association with cognitive outcomes. Similar results were observed with six other gray matter hubness measures. This suggests that damage to densely connected white matter regions is more cognitively impairing than similar damage to gray matter hubs, helping to explain interindividual differences in cognitive outcomes after brain damage.

The importance of different brain regions in supporting large-scale brain networks is not uniformly distributed. Hub regions are especially critical in forming a backbone of global network architecture and, by extension, are thought to be critical in supporting human cognition. However, there are competing ideas regarding what measures of “hubness” are most relevant for cognition (1, 2). Much of the evidence linking structural and functional hubs to cognition is correlational in nature, showing associations of imaging measures with task performance in healthy participants (3). While informative, it is difficult to draw causal inferences from these studies. As such, studies of neurological patients with focal pathology have been helpful in further clarifying the role of network hubs in cognition (4–7).Influential studies have shown that focal brain damage involving network hubs causes widespread changes in brain networks (8–10). In addition, some studies have related hub damage with cognitive impairment, either in a single domain (7, 11) or spanning multiple cognitive domains (6, 12). These studies have largely focused on either gray matter measures (6) or white matter measures of hubness (13) but have not compared the two. Here, we aim to extend this line of research by quantifying the degree to which individuals’ focal brain lesions map onto both functional and structural network measures of hubness in two large cohorts. We focus on two well-established network metrics, participation coefficient and edge density—derived from gray and white matter, respectively—to test the association of these network measures with general cognitive performance.Participation coefficient describes the involvement of a brain region within multiple brain systems. It is often considered the preferred measure of “hubness” in networks derived from correlated patterns of brain activity, including those derived from resting state functional connectivity MRI (8). Regions with higher participation coefficient are thought to be important for integrating and coordinating processing between networks, a feature that may be important for general cognitive processes (14–16). For instance, Warren and colleagues (6) assessed the postlesion performance of 30 patients with focal damage to regions either high or low in participation coefficient, derived from normative functional connectivity MRI data. Patients with lesions in high participation coefficient regions showed broad cognitive impairments in multiple domains, beyond what was expected by clinicians based on lesion location alone (6, 17).Alternatively, regions with a high density of white matter connections also form structural network hubs, as these regions are critical for facilitating the flow of information in brain networks. Edge density provides an important metric of this kind of structural hubness, indexing the number of white matter connectome edges that link gray matter regions on a voxel-wise basis (18). Introducing lesions to regions high in edge density in the posterior periventricular white matter was disruptive to distributed brain networks in simulated lesion analyses (19, 20), but this has yet to be tested with data from patients with brain lesions.The relative importance of these gray and white matter network measures in identifying brain regions important for human cognition is unclear. Lesion studies that have looked at this topic have relatively small sample sizes and focus on gray or white matter network measures, but not both. There is some evidence to suggest, however, that white matter network metrics might be more predictive of cognitive outcomes than those derived from gray matter (13, 21–23). For instance, a study by Griffis and colleagues (7) found that damage to white matter “bottlenecks” underlying the temporal lobe was more predictive of language impairment than damage to canonical cortical regions involved in language. However, a systematic evaluation that evaluates both structural and functional network hubness measures as they relate to cognitive outcomes is needed to further evaluate the relative importance of each.Here, we extend this line of investigation by evaluating the real-world functional importance of different types of structural and functional network hubs based on their association with cognitive impairment following focal brain lesions. In two large cohorts of individuals with focal, acquired brain lesions (N = 402 and 102), we estimated the degree to which the brain lesions disrupt brain networks based on the extent of the lesion’s overlap with population-derived, brain-wide maps of edge density and participation coefficient. We estimated general cognition in each subject based on shared variance in a structural equation model among 17 neuropsychological tests spanning different domains of cognition. Based on the evidence reviewed above, we hypothesized that greater cognitive deficits would be seen in association with 1) lesions of gray matter regions that participate in multiple networks (represented as higher participation coefficient), 2) lesions of densely connected white matter (represented as higher edge density), and 3) a regression model combining edge density and participation coefficient would provide a stronger prediction than either measure alone, with edge density explaining more variance in cognitive outcomes relative to participation coefficient (8, 9, 21). Prior to conducting any analyses, we preregistered these three main hypotheses and the proposed analytic approach on the Open Science Framework (OSF) (https://osf.io/kpc2b/?view_only=a38cd1e09a4f4735b02cb36955c3f933).     

TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis

BACKGROUND: Therapeutic strategies to block tumour necrosis factor alpha (TNFalpha) activity in experimental autoimmune arthritis models and rheumatoid arthritis (RA) have proved highly successful, and provide sustained beneficial effects. OBJECTIVE: To examine whether TNFalpha inhibition has immunological activity beyond the reduction of inflammation in collagen induced arthritis (CIA), an established experimental model of RA. METHODS: Arthritic DBA/1 mice received single periarticular injections of retroviral constructs encoding human TNF receptor (TNF-R) into the affected arthritic paw, at the onset of arthritis. Severity of arthritis, antibodies to collagen type II (CII), and extent of pathological joint damage of arthritic paws were compared between TNF-R and media treated (control) animals 3, 7, 14, 21, and 49 days after disease onset. RESULTS: Severity of CIA was significantly decreased in TNF-R treated animals compared with controls, 14-34 days after disease onset. Joint destruction was reduced in TNF-R injected joints and in the uninjected contralateral and ipsilateral paws of TNF-R treated animals. Seven days after disease onset, TNF-R treated mice had lower levels of inflammatory Th1 driven IgG2a antibodies to CII (p<0.05) than controls. This altered the anticollagen IgG2a:IgG1 ratio towards Th2 driven IgG1. CONCLUSIONS: Local TNF-R gene therapy in CIA appears to have systemic effects on the anti-CII antibodies. The overall influence of TNF-R gene therapy is that it inhibits the progression of CIA mainly by suppressing the inflammatory Th1 response rather than by stimulating a Th2 response. Therefore, periarticular TNF-R gene therapy may have excellent therapeutic potential in RA.     

Therapy of severe aplastic anemia in young adults and children with allogeneic bone marrow transplantation

During an 8-year period, 28 young adults (median age 27 years) and 30 children (median age 10 years) with severe aplastic anemia have received allogeneic bone marrow transplantation (BMT) from major histocompatibility locimatched sibling donors after preparation with cyclophosphamide and total lymphoid irradiation (TLI). All recipients were previously transfused. Comparison of post-bone marrow transplantation events in adults and children reveals equivalent median time to engraftment, median duration of hospitalization, median Karnofsky assessment of activity, and equivalent low rejection rate. Although the incidence of moderate and severe acute graft-v-host disease (GVHD) and of extensive chronic GVHD was greater in adults than in children, the projected survival at 4 years of adults (67%; 95% confidence interval [CI] 49% to 85%) and of children (73%; 95% CI 57% to 89%) was equivalent. All survivors are transfusion-free and have normal peripheral blood counts. One of 28 adults and 2 of 30 children have experienced rejection, and 1 of these patients survives after a second transplant. No malignancies have been identified following transplantation. An unexpectedly high incidence of hypothyroidism has been detected and may be attributable to preparation of recipients with TLI. Therapy of severe aplastic anemia with allogeneic BMT after preparation with cyclophosphamide and TLI offers a high rate of transfusion-free survival and a low rejection rate in previously transfused young adults and children.     

Superficial femoral artery occlusion: nitinol stents achieve better flow and reduce the need for medications than balloon angioplasty alone

BACKGROUND: Nitinol slotted tube stents are of great potential benefit in superficial femoral artery (SFA) interventions due to their elastic properties. However, a paucity of data exists for their efficacy in total SFA occlusions. METHODS: Using the Cleveland Clinic Foundation Peripheral Database, we identified 40 consecutive patients who underwent percutaneous revascularization for chronically occluded SFA and addressed the outcome stratifying for stent use. We evaluated the reduction in the pressure gradient across the lesion and the need for medication following revascularization. RESULTS: Of the 40 patients, twenty-six underwent balloon angioplasty alone and 14 received nitinol slotted tube stents. Patients were well matched for age and cardiovascular risk factors. Similarly, there were no differences in baseline ankle brachial index (ABI) or claudication class between the groups. Compared to angioplasty alone, stenting was associated with a greater reduction in translesional pressure gradient (72 mmHg versus 32 mmHg; p = 0.002). In addition, patients treated with stents were less likely to require post-procedure adjunctive medical treatment (7.1% versus 42.6%; p = 0.03). CONCLUSION: In SFA occlusion, stenting results in greater reduction in translesional pressure gradient and reduced need for adjunctive medical treatment.     

Investigation of an outbreak of Japanese encephalitis in Rourkela City (Orissa) during 1989.

An outbreak of Japanese encephalitis (JE) was reported from Rourkela city for the first time in September-November 1989. 41 cases and 15 deaths occurred with a case fatality rate of 36.6 per cent. Most of the cases (66 per cent) were in the age group of 5-19 years. There was no case under 5 years. Female-male ratio of cases was 1:1.7. Serological examination of convalescent cases showed JE specific IgM indicating strong evidence of recent JE infection. Large number of pigs were seen in the affected areas.     

Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.