Jeffrey S. Spence

Neural Mechanisms of Brain Plasticity with Complex Cognitive Training in Healthy Seniors

Complex mental activity induces improvements in cognition, brain function, and structure in animals and young adults. It is not clear to what extent the aging brain is capable of such plasticity. This study expands previous evidence of generalized cognitive gains after mental training in healthy seniors. Using 3 MRI-based measurements, that is, arterial spin labeling MRI, functional connectivity, and diffusion tensor imaging, we examined brain changes across 3 time points pre, mid, and post training (12 weeks) in a randomized sample (n = 37) who received cognitive training versus a control group. We found significant training-related brain state changes at rest; specifically, 1) increases in global and regional cerebral blood flow (CBF), particularly in the default mode network and the central executive network, 2) greater connectivity in these same networks, and 3) increased white matter integrity in the left uncinate demonstrated by an increase in fractional anisotropy. Improvements in cognition were identified along with significant CBF correlates of the cognitive gains. We propose that cognitive training enhances resting-state neural activity and connectivity, increasing the blood supply to these regions via neurovascular coupling. These convergent results provide preliminary evidence that neural plasticity can be harnessed to mitigate brain losses with cognitive training in seniors.

Regionally Selective Atrophy after Traumatic Axonal Injury

OBJECTIVES To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome. DESIGN Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging-based morphometric analysis. SETTING Inpatient traumatic brain injury unit. PATIENTS OR OTHER PARTICIPANTS Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls. MAIN OUTCOME MEASURE Changes in global and regional brain volumes between initial and follow-up magnetic resonance imaging were used to assess the spatial distribution of posttraumatic volume loss. The Glasgow Outcome Scale-Extended score was the primary measure of functional outcome. RESULTS Patients underwent substantial global atrophy with mean whole-brain parenchymal volume loss of 4.5% (95% confidence interval, 2.7%-6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole-brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus. CONCLUSION Traumatic axonal injury leads to substantial posttraumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.

Assessing Spatial Relationships between Axonal Integrity, Regional Brain Volumes, and Neuropsychological Outcomes after Traumatic Axonal Injury

Diffuse traumatic axonal injury (TAI) is a type of traumatic brain injury (TBI) characterized predominantly by white matter damage. While TAI is associated with cerebral atrophy, the relationship between gray matter volumes and TAI of afferent or efferent axonal pathways remains unknown. Moreover, it is unclear if deficits in cognition are associated with post-traumatic brain volumes in particular regions. The goal of this study was to determine the relationship between markers of TAI and volumes of cortical and subcortical structures, while also assessing the relationship between cognitive outcomes and regional brain volumes. High-resolution magnetic resonance imaging scans were performed in 24 patients with TAI within 1 week of injury and were repeated 8 months later. Diffusion tensor imaging (DTI) tractography was used to reconstruct prominent white matter tracts and calculate their fractional anisotropy (FA) and mean diffusivity (MD) values. Regional brain volumes were computed using semi-automated morphometric analysis. Pearsons correlation coefficients were used to assess associations between brain volumes, white matter integrity (i.e., FA and MD), and neuropsychological outcomes. Post-traumatic volumes of many gray matter structures were associated with chronic damage to related white matter tracts, and less strongly associated with measures of white matter integrity in the acute scans. For example, left and right hippocampal volumes correlated with FA in the fornix body (r = 0.600, p = 0.001; r = 0.714, p < 0.001, respectively). In addition, regional brain volumes were associated with deficits in corresponding neuropsychological domains. Our results suggest that TAI may be a primary mechanism of post-traumatic atrophy, and provide support for regional morphometry as a biomarker for cognitive outcome after injury.

Deficits in Functional Connectivity of Hippocampal and Frontal Lobe Circuits after Traumatic Axonal Injury

OBJECTIVE To examine the functional connectivity of hippocampal and selected frontal lobe circuits in patients with traumatic axonal injury (TAI). DESIGN Observational study. SETTING An inpatient traumatic brain injury unit. Imaging and neurocognitive assessments were conducted in an outpatient research facility. PARTICIPANTS Twenty-five consecutive patients with brain injuries consistent with TAI and acute subcortical white matter abnormalities were studied as well as 16 healthy volunteers of similar age and sex. INTERVENTIONS Echo-planar and high-resolution T1-weighted images were acquired using 3-T scanners. Regions of interest (ROI) were drawn bilaterally for the hippocampus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex and were used to extract time series data. Blood oxygenation level-dependent data from each ROI were used as reference functions for correlating with all other brain voxels. Interhemispheric functional connectivity was assessed for each participant by correlating homologous regions using a Pearson correlation coefficient. Patient functional and neurocognitive outcomes were assessed approximately 6 months after injury. MAIN OUTCOME MEASURES Interhemispheric functional connectivity, spatial patterns of functional connectivity, and associations of connectivity measures with functional and neurocognitive outcomes. RESULTS Patients showed significantly lower interhemispheric functional connectivity for the hippocampus and ACC. Controls demonstrated stronger and more focused functional connectivity for the hippocampi and ACC, and a more focused recruitment of the default mode network for the dorsolateral prefrontal cortex ROI. The interhemispheric functional connectivity for the hippocampus was correlated with delayed recall of verbal information. CONCLUSIONS Traumatic axonal injury may affect interhemispheric neural activity, as patients with TAI show disrupted interhemispheric functional connectivity. More careful investigation of interhemispheric connectivity is warranted, as it demonstrated a modest association with outcome in chronic TBI.

Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge

PURPOSE To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. MATERIALS AND METHODS The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. RESULTS Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. CONCLUSION Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.

Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses

Object Coagulopathy and thrombocytopenia are common after traumatic brain injury (TBI), yet transfusion thresholds for mildly to moderately abnormal ranges of international normalized ratio and platelet count remain controversial. This study evaluates associations between fresh frozen plasma (FFP) and platelet transfusions with long-term functional outcome and survival in TBI patients with moderate hemostatic laboratory abnormalities. Methods This study is a retrospective review of prospectively collected data of patients with mild to severe TBI. Data include patient demographics, several initial injury severity metrics, daily laboratory values, Glasgow Outcome Score- Extended (GOSE) scores, Functional Status Examination (FSE) scores, and survival to 6 months. Correlations were evaluated between these variables and transfusion of FFP, platelets, packed red blood cells (RBCs), cryoprecipitate, recombinant factor VIIa, and albumin. Ordinal regression was performed to account for potential confounding variables to further define relationships between transfusion status and long-term outcome. By analyzing collected data, mild to moderate coagulopathy was defined as an international normalized ratio 1.4-2.0, moderate thrombocytopenia as platelet count 50 × 10(9)/L to 107 × 10(9)/L, and moderate anemia as 21%-30% hematocrit. Results In patients with mild to moderate laboratory hematological abnormalities, univariate analysis shows significant correlations between poor outcome scores and FFP, platelet, or packed RBC transfusion; the volume of FFP or packed RBCs transfused also correlated with poor outcome. Several measures of initial injury and laboratory abnormalities also correlated with poor outcome. Patient age, initial Glasgow Coma Scale score, and highest recorded serum sodium were included in the ordinal regression model using backward variable selection. In the moderate coagulopathy subgroup, patients transfused with FFP were more likely to have a lower GOSE score relative to those who did not receive a transfusion (OR 5.20 [95% CI 1.72-15.73]). Patients with moderate coagulopathy who received FFP and packed RBCs were even more likely to be have a lower GOSE score (OR 7.17 [95% CI 2.12-24.12]). Moderately anemic patients who received packed RBCs alone were more likely to have a worse long-term functional outcome as determined by GOSE and FSE scores (GOSE: OR 2.41 [95% CI 1.51-3.85]; and FSE: OR 3.27 [95% CI 2.00-5.35]). No transfusion types or combinations were noted to significantly correlate with the 6-month mortality in ordinal regression. Conclusions In TBI patients with moderate coagulopathy, FFP transfusions alone or a combination of FFP and packed RBCs were associated with poorer long-term functional outcomes as measured by the GOSE. Red blood cell transfusions were associated with poor long-term functional outcome in TBI patients with moderate anemia. Platelet transfusion in patients with moderate thrombocytopenia was not significantly associated with outcome. Although transfusion is beneficial to many patients with severe hematological abnormalities, it is not without risk, and the indications for transfusion should be carefully considered in patients with moderate hematological abnormalities.

Imaging Correlates of Memory and Concussion History in Retired National Football League Athletes

IMPORTANCE To our knowledge, this is the first study to show an association between concussion, cognition, and anatomical structural brain changes across the age spectrum in former National Football League athletes. OBJECTIVE To assess the relationship of hippocampal volume, memory performance, and the influence of concussion history in retired National Football League athletes with and without mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study assessed differences between groups, mean hippocampal volumes, and memory performance by computing age quintiles based on group-specific linear regression models corrected for multiple comparisons for both athletes and control participants. The study was conducted starting in November 2010 and is ongoing at a research center in the northern region of Texas. This current analysis was conducted from October 9, 2013, to August 21, 2014. Participants included 28 retired National Football League athletes, 8 of whom had MCI and a history of concussion, 21 cognitively healthy control participants, and 6 control participants with MCI without concussion. MAIN OUTCOMES AND MEASURES Hippocampal volume, age, California Verbal Learning Test scores, and the number of grade 3 (G3) concussions. In addition, the number of games played was examined as an objective variable pertaining to football history. RESULTS The mean (SD) age was 58.1 (13) years for the 28 former athletes and 59.0 (12) years for the 27 control participants. Retired athletes with concussion history but without cognitive impairment had normal but significantly lower California Verbal Learning Test scores compared with control participants (mean [SD], 52.5 [8] vs 60.24 [7]; P = .002); those with a concussion history and MCI performed worse (mean [SD], 37 [8.62]) compared with both control participants (P < .001) and athletes without memory impairment (P < .001). Among the athletes, 17 had a G3 concussion and 11 did not. Older retired athletes with at least 1 G3 concussion had significantly smaller bilateral hippocampal volumes compared with control participants at the 40th age percentile (left, P = .04; right, P = .03), 60th percentile (left, P = .009; right, P = .01), and 80th percentile (left, P = .001; right, P = .002) and a smaller right hippocampal volume compared with athletes without a G3 concussion at the 40th percentile (P = .03), 60th percentile (P = .02), and 80th percentile (P = .02). Athletes with a history of G3 concussion were more likely to have MCI (7 of 7) compared with retired athletes without a history of G3 concussion (1 of 5) older than 63 years (P = .01). In addition, the left hippocampal volume in retired athletes with MCI and concussion was significantly smaller compared with control participants with MCI (P = .03). CONCLUSION AND RELEVANCE Prior concussion that results in loss of consciousness is a risk factor for increased hippocampal atrophy and the development of MCI. In individuals with MCI, hippocampal volume loss appears greater among those with a history of concussion.

Frontal theta and alpha power and coherence changes are modulated by semantic complexity in Go/NoGo tasks

To study the interactions between semantic processing and motor response inhibition, we recorded scalp EEG as subjects performed a series of Go/NoGo response inhibition tasks whose response criteria depended on different levels of semantic processing. Three different tasks were used. The first required the subject to make a Go/NoGo decision based on pictures of one particular car or one particular dog. The second used pictures of different types of cars and of dogs, and the final task used stimuli that ranged across multiple types of objects and animals. We found that the theta-band EEG power recorded during the NoGo response was attenuated as a function of semantic complexity while the peak latency was delayed in only the most complex category task. Further, frontal alpha-band desynchronization was strongest for the simplest task and remained close to baseline for the other tasks. Finally, there was significant theta-band coherence between the frontal pole and pre-SMA for the NoGo conditions across tasks, which was not found in the Go trials. These findings provide information about how more rostral frontal regions interact with the pre-SMA during response inhibition across different stimuli and task demands: specifically, level of processing affects latency, difficulty affects amplitude, and coherence is affected by whether the decision is Go or NoGo.

Perfusion deficit to cholinergic challenge in veterans with Gulf War Illness

A highly plausible etiology for Gulf War Illness (GWI) is that the neural damage and cognitive deficits are associated with excessive exposure to cholinesterase-inhibiting cholinergic stimulants. Our previous SPECT study provided strong indication that cerebral blood flow (CBF) in veterans with GWI may be different from those of unaffected control veterans. The present study confirmed and extended previous findings that patients with GWI have abnormal response to an inhibitory cholinergic challenge, physostigmine infusion, when compared to age-gender-education matched control veterans. The MRI-based arterial spin labeling (ASL) and phase-contrast techniques have several key advantages over SPECT, including shorter experiment duration, complete non-invasiveness, and higher spatial and temporal resolutions, and therefore may provide a cost-effective biomarker for characterization of GWI.

Using a white matter reference to remove the dependency of global signal on experimental conditions in SPECT analyses

Proportional scaling models are often used in functional imaging studies to remove confounding of local signals by global effects. It is generally assumed that global effects are uncorrelated with experimental conditions. However, when the global effect is estimated by the global signal, defined as the intracerebral average, incorrect inference may result from the dependency of the global signal on preexisting conditions or experimental manipulations. In this paper, we propose a simple alternative method of estimating the global effect to be used in a proportional scaling model. Specifically, by defining the global signal with reference strictly to a white matter region within the centrum semiovale, the dependency is removed in experiments where white matter is unaffected by the disease effect or experimental treatments. The increase in the ability to detect changes in regional blood flow is demonstrated in a SPECT study of healthy and ill Gulf War veterans in whom it is suspected that brain abnormalities influence the traditional calculation of the global signal. Controlling for the global effect, ill veterans have significantly lower intracerebral averages than healthy controls (P = 0.0038), evidence that choice of global signal has an impact on inference. Scaling by the modified global signal proposed here results in an increase in sensitivity leading to the identification of several regions in the insula and frontal cortex where ill veterans have significantly lower SPECT emissions. Scaling by the traditional global signal results in the loss of sensitivity to detect these regional differences. Advantages of this alternative method are its computational simplicity and its ability to be easily integrated into existing analysis frameworks such as SPM.