Showing papers in "Brain Imaging and Behavior in 2015"

Traumatic brain injury in the US military: epidemiology and key clinical and research programs

Abstract: Traumatic brain injury (TBI), and particularly concussion, is a major concern for the U.S. Military because of the associated short term disability, long term cognitive and pain symptoms suffered by some, and risk of prolonged or permanent neurologic injury if the Service member incurs a second TBI before full recovery from the first. Concussions were seen more often during the recent conflicts in Afghanistan and Iraq than in prior conflicts, such as the Vietnam War, because of the use of improvised explosive devices that typically caused non-penetrating closed head injury. Since 2000 more than 300,000 Service members were diagnosed with TBI, of which more than 80 % were concussions. Improved TBI screening tools also have identified a higher than expected incidence of concussions occurring in garrison. In this review we summarize current epidemiologic data for TBI in the Military, and describe contemporary Military procedures and strategies for TBI prevention, identification, evaluation, and acute and chronic care. Key TBI clinical research priorities and programs are described, and innovative organizational plans to address future TBI needs are summarized.

Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans.

Abstract: Recent research has examined the effects of oxytocin (OT) and vasopressin (AVP) on human social behavior and brain function. However, most participants have been male, while previous research in our lab demonstrated sexually differentiated effects of OT and AVP on the neural response to reciprocated cooperation. Here we extend our previous work by significantly increasing the number of participants to enable the use of more stringent statistical thresholds that permit more precise localization of OT and AVP effects in the brain. In a double-blind, placebo-controlled study, 153 men and 151 women were randomized to receive 24 IU intranasal OT, 20 IU intranasal AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Sex differences were observed for effects of OT on the neural response to reciprocated cooperation, such that OT increased the caduate/putamen response among males, whereas it decreased this response among females. Thus, 24 IU OT may increase the reward or salience of positive social interactions among men, while decreasing their reward or salience among women. Similar sex differences were also observed for AVP effects within bilateral insula and right supramarginal gyrus when a more liberal statistical threshold was employed. While our findings support previous suggestions that exogenous nonapeptides may be effective treatments for disorders such as depression and autism spectrum disorder, they caution against uniformly extending such treatments to men and women alike.

Meta-analyses of structural regional cerebral effects in type 1 and type 2 diabetes

Abstract: Diabetes is associated with macrovascular and microvascular complications and is a major risk factor for neurological and psychiatric disorders, such as dementia and depression. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) have distinct etiologies and pathophysiological effects while sharing a common endpoint of persistent hyperglycemia. Neuroimaging studies in T1DM have revealed reductions in numerous regions, including the parahippocampal and occipital regions, while in T2DM there have been numerous reports of hippocampal atrophy. This meta-analysis aimed to identify consistent regional abnormalities in cerebral structures in T1DM and T2DM respectively, and also to examine the impact of potential confounds, including age, depression and vascular risk factors. Neuroimaging studies of both voxel-based morphometry (VBM) data and volumetric data were included. Ten T1DM studies (n = 613 patients) and 23 T2DM studies (n = 1364 patients) fulfilled inclusion criteria. The T1DM meta-analysis revealed reduced bilateral thalamus grey matter density in adults. The T2DM meta-analysis revealed reduced global brain volume and regional atrophy in the hippocampi, basal ganglia, and orbitofrontal and occipital lobes. Moreover, hippocampal atrophy in T2DM was not modified by hypertension, although there were more marked reductions in younger patients relative to healthy controls. In conclusion, T1DM and T2DM demonstrated distinct cerebral effects with generalised and specific target areas of grey matter reduction. Thalamic atrophy in T1DM may be a substrate of associated cognitive deficits. In T2DM, global cerebral atrophy may reflect atherosclerotic factors, while hippocampal atrophy was an independent effect providing a potential common neuropathological etiology for the comorbidity of T2DM with dementia and depression.

Treatment of persistent post-concussive symptoms after mild traumatic brain injury: a systematic review of cognitive rehabilitation and behavioral health interventions in military service members and veterans

Abstract: Increased prevalence of traumatic brain injury (TBI) has been associated with service members and veterans who completed combat deployments in support of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) Management of persistent post-concussive symptoms (PCS) has been a challenge to healthcare providers throughout the Military and Veterans Healthcare Systems, as well as civilian healthcare providers, due in part to the chronic nature of symptoms, co-occurrence of behavioral health disorders such as depression, Posttraumatic Stress Disorder (PTSD), and substance use disorders, and fear of a potential stigma associated with psychiatric diagnoses and behavioral health treatment(s) This systematic review examined non-pharmacologic behavioral health interventions and cognitive rehabilitation interventions for PCS in military service members and veterans with a history of mild TBI (mTBI) Six electronic databases were searched with specific term limitations, identifying 121 citations Ultimately, 19 articles met criteria for inclusion in this systematic review Studies were broadly categorized into four subtypes: psychoeducational interventions, cognitive rehabilitation, psychotherapeutic approaches, and integrated behavioral health interventions for PCS and PTSD The review provides an update of the empirical evidence for these four types of interventions for PCS in active duty service members and veterans Recommendations for future research are discussed, including the need to expand and improve the limited evidence basis on how to manage persistent post-concussive symptoms in this population

Multimodal manifold-regularized transfer learning for MCI conversion prediction

Abstract: As the early stage of Alzheimer's disease (AD), mild cognitive impairment (MCI) has high chance to convert to AD. Effective prediction of such conversion from MCI to AD is of great importance for early diagnosis of AD and also for evaluating AD risk pre-symptomatically. Unlike most previous methods that used only the samples from a target domain to train a classifier, in this paper, we propose a novel multimodal manifold-regularized transfer learning (M2TL) method that jointly utilizes samples from another domain (e.g., AD vs. normal controls (NC)) as well as unlabeled samples to boost the performance of the MCI conversion prediction. Specifically, the proposed M2TL method includes two key components. The first one is a kernel-based maximum mean discrepancy criterion, which helps eliminate the potential negative effect induced by the distributional difference between the auxiliary domain (i.e., AD and NC) and the target domain (i.e., MCI converters (MCI-C) and MCI non-converters (MCI-NC)). The second one is a semi-supervised multimodal manifold-regularized least squares classification method, where the target-domain samples, the auxiliary-domain samples, and the unlabeled samples can be jointly used for training our classifier. Furthermore, with the integration of a group sparsity constraint into our objective function, the proposed M2TL has a capability of selecting the informative samples to build a robust classifier. Experimental results on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database validate the effectiveness of the proposed method by significantly improving the classification accuracy of 80.1 % for MCI conversion prediction, and also outperforming the state-of-the-art methods.

Cardiorespiratory fitness is associated with brain structure, cognition, and mood in a middle-aged cohort at risk for Alzheimer's disease.

Abstract: Cardiorespiratory fitness (CRF) is an objective measure of habitual physical activity (PA), and has been linked to increased brain structure and cognition. The gold standard method for measuring CRF is graded exercise testing (GXT), but GXT is not feasible in many settings. The objective of this study was to examine whether a non-exercise estimate of CRF is related to gray matter (GM) volumes, white matter hyperintensities (WMH), cognition, objective and subjective memory function, and mood in a middle-aged cohort at risk for Alzheimer’s disease (AD). Three hundred and fifteen cognitively healthy adults (mean age =58.58 years) enrolled in the Wisconsin Registry for Alzheimer’s Prevention underwent structural MRI scanning, cognitive testing, anthropometric assessment, venipuncture for laboratory tests, and completed a self-reported PA questionnaire. A subset (n = 85) underwent maximal GXT. CRF was estimated using a previously validated equation incorporating sex, age, body-mass index, resting heart rate, and self-reported PA. Results indicated that the CRF estimate was significantly associated with GXT-derived peak oxygen consumption, validating its use as a non-exercise CRF measure in our sample. Support for this finding was seen in significant associations between the CRF estimate and several cardiovascular risk factors. Higher CRF was associated with greater GM volumes in several AD-relevant brain regions including the hippocampus, amygdala, precuneus, supramarginal gyrus, and rostral middle frontal gyrus. Increased CRF was also associated with lower WMH and better cognitive performance in Verbal Learning & Memory, Speed & Flexibility, and Visuospatial Ability. Lastly, CRF was negatively correlated with self- and informant-reported memory complaints, and depressive symptoms. Together, these findings suggest that habitual participation in physical activity may provide protection for brain structure and cognitive function, thereby decreasing future risk for AD.

Functional neuroimaging of acute oculomotor deficits in concussed athletes

Abstract: In the pursuit to better understand the neural underpinnings of oculomotor deficits following concussion we performed a battery of oculomotor tests while performing simultaneous functional magnetic resonance imaging (fMRI). Based on the increasing evidence that concussion can disrupt multiple brain functional networks, including the oculomotor control networks, a series of classic saccadic and smooth pursuit tasks were implemented. Nine concussed athletes were tested within seven days of injury along with nine age and sex matched healthy normal volunteers. Both behavioral and fMRI data revealed differential results between the concussed and normal volunteer groups. Concussed subjects displayed longer latency time in the saccadic tasks, worse position errors, and fewer numbers of self-paced saccades compared to normal volunteer subjects. Furthermore, the concussed group showed recruitment of additional brain regions and larger activation sites as evidenced by fMRI. As a potential diagnostic and management tool for concussion, oculomotor testing shows promise, and here we try to understand the reasons for this disrupted performance with the aide of advanced neuroimaging tools.

Advanced neuroimaging applied to veterans and service personnel with traumatic brain injury: state of the art and potential benefits

Abstract: Traumatic brain injury (TBI) remains one of the most prevalent forms of morbidity among Veterans and Service Members, particularly for those engaged in the conflicts in Iraq and Afghanistan. Neuroimaging has been considered a potentially useful diagnostic and prognostic tool across the spectrum of TBI generally, but may have particular importance in military populations where the diagnosis of mild TBI is particularly challenging, given the frequent lack of documentation on the nature of the injuries and mixed etiologies, and highly comorbid with other disorders such as post-traumatic stress disorder, depression, and substance misuse. Imaging has also been employed in attempts to understand better the potential late effects of trauma and to evaluate the effects of promising therapeutic interventions. This review surveys the use of structural and functional neuroimaging techniques utilized in military studies published to date, including the utilization of quantitative fluid attenuated inversion recovery (FLAIR), susceptibility weighted imaging (SWI), volumetric analysis, diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), positron emission tomography (PET), magnetoencephalography (MEG), task-based and resting state functional MRI (fMRI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). The importance of quality assurance testing in current and future research is also highlighted. Current challenges and limitations of each technique are outlined, and future directions are discussed.

Neurotoxicity in breast cancer survivors ≥10 years post-treatment is dependent on treatment type

Abstract: Adjuvant chemotherapy (CT) for breast cancer (BC) is associated with very late side-effects on brain function and structure. However, little is known about neurotoxicity of specific treatment regimens. To compare neurotoxicity profiles after different treatment strategies, we used neurocognitive testing and multimodality MRI in BC survivors randomized to high-dose (HI), conventional-dose (CON-) CT or radiotherapy (RT) only and a healthy control (HC) group. BC survivors who received CON-CT (n = 20) and HC (n = 20) were assessed using a neurocognitive test battery and multimodality MRI including 3D-T1, Diffusion Tensor Imaging (DTI) and 1H-MR spectroscopy (1H-MRS) to measure various aspects of cerebral white (WM) and gray matter (GM). Data were compared to previously assessed groups of BC survivors who received HI-CT (n = 17) and RT-only (n = 15). Testing took place on average 11.5 years post-CT. 3D-T1 showed focal GM volume reductions both for HI-CT and CON-CT compared to RT-only (p < .004). DTI-derived mean diffusivity and 1H-MRS derived N-acetyl aspartate showed WM injury specific to HI-CT but not CON-CT (p < .05). Residual effects were revealed in the RT-only group compared to HC on MRI and neurocognitive measurements (p < .05). Ten years after adjuvant CT for BC lower cerebral GM volume was found in HI as well as CON-CT BC survivors whereas injury to WM is restricted to HI-CT. This might indicate that WM brain changes after BC treatment may show more pronounced (partial) recovery than GM. Furthermore, our results suggest residual neurotoxicity in the RT-only group, which warrants further investigation.

Gender differences in affective sharing and self-other distinction during empathic neural responses to others' sadness

Abstract: Self–other distinction, the separation between self and other, is a prerequisite for empathy through which individuals share another individual’s feelings. Prior research suggests that females are better at recognizing and sharing others’ emotions, whereas males perform better at self–other distinction. It is unclear, however, whether this superiority in the self–other distinction occurs in males throughout the experience of empathy or only at some stages of the empathic process. The present study utilized event–related potentials (ERPs) to investigate this issue. In two separate experimental tasks, subjects were instructed to either judge the emotions shown on a face (other–task) or evaluate their own affective responses to the emotions shown on a face (self–task). The results of the other–task revealed that unlike males, females displayed increased P2 (190–240 ms) amplitudes to sad expressions compared with neutral expressions. This finding might be associated with an improved ability to recognize and share the emotions of others in females. In contrast, only males exhibited larger P2 amplitudes to sad expressions compared with neutral expressions during the self–task. This awareness of one’s own emotions in response to another individual might reflect a distinction between the self and the other at an early stage in males. At the late cognitive controlled stage, gender differences became weak. However, the emotion effects in each task for both genders were positively correlated with self-reported cognitive empathy, which was indexed by the perspective taking (PT) and fantasy (FS) subscale, but not with affective empathy.

Neuroimaging as a biomarker in symptom validity and performance validity testing

Abstract: How neuropsychological assessment findings are deemed valid has been a topic of numerous articles but few have addressed any role that neuroimaging studies could provide. Within military and various clinical samples of individuals undergoing neuropsychological evaluations, high levels of failure on measures of symptom validity testing (SVT) and/or performance validity testing (PVT) have been reported. Where ‘failure’ is defined as a below cut-score performance on some pre-determined set-point on a SVT/PVT measure, are such failures always indicative of invalid test findings or are there other explanations, especially based on informative neuroimaging findings? This review starts with the premise that even though the SVT/PVT task is designed to be simple and easy to perform, it nonetheless requires intact frontoparietal attention, working memory and task engagement (motivation) networks. If there is damage or pathology within any aspect of these networks as demonstrated by neuroimaging findings, the patient may perform below the cut-point as a result of the underlying damage or pathophysiology. The argument is made that neuroimaging findings should be considered as to where SVT/PVT cut-points are established and there should be much greater flexibility in SVT/PVT measures based on other personal, demographic and neuroimaging information. Several case studies are used to demonstrate these points.

Modification of EEG functional connectivity and EEG power spectra in overweight and obese patients with food addiction: An eLORETA study.

Abstract: We evaluated the modifications of electroencephalographic (EEG) power spectra and EEG connectivity in overweight and obese patients with elevated food addiction (FA) symptoms. Fourteen overweight and obese patients (3 men and 11 women) with three or more FA symptoms and fourteen overweight and obese patients (3 men and 11 women) with two or less FA symptoms were included in the study. EEG was recorded during three different conditions: 1) five minutes resting state (RS), 2) five minutes resting state after a single taste of a chocolate milkshake (ML-RS), and 3) five minutes resting state after a single taste of control neutral solution (N-RS). EEG analyses were conducted by means of the exact Low Resolution Electric Tomography software (eLORETA). Significant modification was observed only in the ML-RS condition. Compared to controls, patients with three or more FA symptoms showed an increase of delta power in the right middle frontal gyrus (Brodmann Area [BA] 8) and in the right precentral gyrus (BA 9), and theta power in the right insula (BA 13) and in the right inferior frontal gyrus (BA 47). Furthermore, compared to controls, patients with three or more FA symptoms showed an increase of functional connectivity in fronto-parietal areas in both the theta and alpha band. The increase of functional connectivity was also positively associated with the number of FA symptoms. Taken together, our results show that FA has similar neurophysiological correlates of other forms of substance-related and addictive disorders suggesting similar psychopathological mechanisms.

Brainstem white matter integrity is related to loss of consciousness and postconcussive symptomatology in veterans with chronic mild to moderate traumatic brain injury.

Abstract: We investigated associations between DTI indices of three brainstem white matter tracts, traumatic brain injury (TBI) injury characteristics, and postconcussive symptomatology (PCS) in a well-characterized sample of veterans with history of mild to moderate TBI (mTBI). 58 military veterans (mTBI: n = 38, mean age = 33.2, mean time since injury = 90.9 months; military controls [MC]; n = 20; mean age = 29.4) were administered 3T DTI scans as well as a comprehensive neuropsychiatric evaluation including evaluation of TBI injury characteristics and PCS symptoms (e.g., negative mood, dizziness, balance and coordination difficulties). Tractography was employed by seeding ROIs along 3 brainstem white matter tracts (i.e., medial lemniscus-central tegmentum tract [ML-CTT]; corticospinal tracts [CST], and pontine tegmentum [PT]), and mean DTI values were derived from fractional anisotropic (FA) maps. Results showed that there were no significant difference in FA between the MC and TBI groups across the 3 regions of interest; however, among the TBI group, CST FA was significantly negatively associated with LOC duration. Additionally, lower FA of certain tracts-most especially the PT-was significantly associated with increased PCS symptoms (i.e., more severe vestibular symptoms, poorer physical functioning, and greater levels of fatigue), even after adjusting for PTSD symptoms. Our findings show that, in our sample of veterans with mTBI, tractography-based DTI indices of brainstem white matter tracts of interest are related to the presence and severity of PCS symptoms. Findings are promising as they show linkages between brainstem white matter integrity and injury severity (LOC), and they raise the possibility that the pontine tegmentum in particular may be a useful marker of PCS symptoms. Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following the 'signature injury' of our combat-exposed veterans.

Heterogeneity of neural mechanisms of response to pivotal response treatment

Abstract: We investigated the mechanisms by which Pivotal Response Treatment (PRT) improves social communication in a case series of 10 preschool-aged children with Autism Spectrum Disorder (ASD). Functional magnetic resonance imaging (fMRI) identified brain responses during a biological motion perception task conducted prior to and following 16 weeks of PRT treatment. Overall, the neural systems supporting social perception in these 10 children were malleable through implementation of PRT; following treatment, neural responses were more similar to those of typically developing children (TD). However, at baseline, half of the children exhibited hypoactivation, relative to a group of TD children, in the right posterior superior temporal sulcus (pSTS), and half exhibited hyperactivation in this region. Strikingly, the groups exhibited differential neural responses to treatment: The five children who exhibited hypoactivation at baseline evidenced increased activation in components of the reward system including the ventral striatum and putamen. The five children who exhibited hyperactivation at baseline evidenced decreased activation in subcortical regions critical for regulating the flow of stimulation and conveying signals of salience to the cortex—the thalamus, amygdala, and hippocampus. Our results support further investigation into the differential effects of particular treatment strategies relative to specific neural targets. Identification of treatment strategies that address the patterns of neural vulnerability unique to each patient is consistent with the priority of creating individually tailored interventions customized to the behavioral and neural characteristics of a given person.

Robust resting state fMRI processing for studies on typical brain development based on multi-echo EPI acquisition

Abstract: Several methodological challenges affect the study of typical brain development based on resting state blood oxygenation level dependent (BOLD) functional MRI (fMRI). One such challenge is mitigating artifacts such as those from head motion, known to be more substantial in younger subjects than older subjects. Other challenges include controlling for potential age-dependence in cerebrospinal fluid (CSF) volume affecting anatomical-functional coregistration; in vascular density affecting BOLD contrast-to-noise; and in CSF pulsation creating time series artifacts. Historically, these confounds have been approached through incorporating artifact-specific temporal and/or spatial filtering into preprocessing pipelines. However, such paths often come with new confounds or limitations. In this study we take the approach of a bottom-up revision of fMRI methodology based on acquisition of multi-echo fMRI and comprehensive utilization of the information in the TE-domain to enhance several aspects of fMRI analysis in the context of a developmental study. We show in a cohort of 25 healthy subjects, aged 9 to 43 years, that the analysis of multi-echo fMRI data eliminates a number of arbitrary processing steps such as bandpass filtering and spatial smoothing, while enabling procedures such as $T_{2}^{*}$ mapping, BOLD contrast normalization and signal dropout recovery, precise anatomical-functional coregistration based on $T_{2}^{*}$ measurements, automatic denoising through removing subject motion, scanner-related signal drifts and physiology, as well as statistical inference for seed-based connectivity. These enhancements are of both theoretical significance and practical benefit in the study of typical brain development.

A resting state functional magnetic resonance imaging study of concussion in collegiate athletes

Abstract: Sports-related concussions are currently diagnosed through multi-domain assessment by a medical professional and may utilize neurocognitive testing as an aid. However, these tests have only been able to detect differences in the days to week post-concussion. Here, we investigate a measure of brain function, namely resting state functional connectivity, which may detect residual brain differences in the weeks to months after concussion. Twenty-one student athletes (9 concussed within 6 months of enrollment; 12 non-concussed; between ages 18 and 22 years) were recruited for this study. All participants completed the Wisconsin Card Sorting Task and the Color-Word Interference Test. Neuroimaging data, specifically resting state functional Magnetic Resonance Imaging data, were acquired to examine resting state functional connectivity. Two sample t-tests were used to compare the neurocognitive scores and resting state functional connectivity patterns among concussed and non-concussed participants. Correlations between neurocognitive scores and resting state functional connectivity measures were also determined across all subjects. There were no significant differences in neurocognitive performance between concussed and non-concussed groups. Concussed subjects had significantly increased connections between areas of the brain that underlie executive function. Across all subjects, better neurocognitive performance corresponded to stronger brain connectivity. Even at rest, brains of concussed athletes may have to ‘work harder’ than their healthy peers to achieve similar neurocognitive results. Resting state brain connectivity may be able to detect prolonged brain differences in concussed athletes in a more quantitative manner than neurocognitive test scores.

Sex differences in orbitofrontal connectivity in male and female veterans with TBI

Abstract: More female soldiers are now serving in combat theaters than at any other time. However, little is known about possible sex differences underlying the neuropathology and manifestation of one of modern war’s signature injuries, traumatic brain injury (TBI). The paucity of information regarding sex differences in TBI is particularly evident when examining changes in executive function and emotion regulation associated with post concussive events. The current study objective was to observe whether patterns of orbitofrontal (OFC) functional connectivity would differ between female veterans with TBI and their male counterparts. The study further sought to determine whether OFC connectivity might be differentially associated with clinical measures of aggression and hostility. Seventeen female veterans and 24 male veterans, age 18 to 25, who met criteria for TBI completed resting state magnetic resonance imaging (MRI) and clinical assessment measures. Imaging data were analyzed using left and right seed regions of the OFC, and regression analyses were conducted to observe the relationship between resting state connectivity and self-reported aggression. Females and males in this study differed in OFC connectivity, with females demonstrating greater connectivity between left and right OFC and parietal and occipital regions and males demonstrating greater connectivity between left and right OFC and frontal and temporal regions. Significant associations between resting state connectivity and clinical measures were found only in male veterans. These findings suggest that TBI may interact with sex-specific patterns of brain connectivity in male and female veterans and exert divergent effects on clinical profiles of aggression post-injury.

Participation in cognitively-stimulating activities is associated with brain structure and cognitive function in preclinical Alzheimer’s disease

Abstract: This study tested the hypothesis that frequent participation in cognitively-stimulating activities, specifically those related to playing games and puzzles, is beneficial to brain health and cognition among middle-aged adults at increased risk for Alzheimer’s disease (AD). Three hundred twenty-nine cognitively normal, middle-aged adults (age range, 43.2–73.8 years) enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) participated in this study. They reported their current engagement in cognitive activities using a modified version of the Cognitive Activity Scale (CAS), underwent a structural MRI scan, and completed a comprehensive cognitive battery. FreeSurfer was used to derive gray matter (GM) volumes from AD-related regions of interest (ROIs), and composite measures of episodic memory and executive function were obtained from the cognitive tests. Covariate-adjusted least squares analyses were used to examine the association between the Games item on the CAS (CAS-Games) and both GM volumes and cognitive composites. Higher scores on CAS-Games were associated with greater GM volumes in several ROIs including the hippocampus, posterior cingulate, anterior cingulate, and middle frontal gyrus. Similarly, CAS-Games scores were positively associated with scores on the Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility domains. These findings were not modified by known risk factors for AD. In addition, the Total score on the CAS was not as sensitive as CAS-Games to the examined brain and cognitive measures. For some individuals, participation in cognitive activities pertinent to game playing may help prevent AD by preserving brain structures and cognitive functions vulnerable to AD pathophysiology.

Hyper-connectivity of the thalamus during early stages following mild traumatic brain injury

Abstract: The thalamo-cortical resting state functional connectivity of seven sub-thalamic regions were examined in a prospectively recruited population of 77 acute mild TBI (mTBI) patients within the first 10 days (mean 6 ± 3 days) of injury and 35 neurologically intact control subjects using the Oxford thalamic connectivity atlas. Neuropsychological assessments were conducted using the Automated Neuropsychological Assessment Metrics (ANAM). A subset of participants received a magentic resonance spectroscopy (MRS) exam to determine metabolite concentrations in the thalamus and the posterior cingulate cortex. Results show that patients performed worse than the control group on various subtests of ANAM and the weighted throughput score, suggesting reduced cognitive performance at this early stage of injury. Both voxel and region of interest based analysis of the resting state fMRI data demonstrated that acute mTBI patients have increased functional connectivity between the various sub-thalamic regions and cortical regions associated with sensory processing and the default mode network (DMN). In addition, a significant reduction in NAA/Cr was observed in the thalamus in the mTBI patients. Furthermore, an increase in Cho/Cr ratio specific to mTBI patients with self-reported sensory symptoms was observed compared to those without self-reported sensory symptoms. These results provide novel insights into the neural mechanisms of the brain state related to internal rumination and arousal, which have implications for new interventions for mTBI patients with persistent symptoms. Furthermore, an understanding of heightened sensitivity to sensory related inputs during early stages of injury may facilitate enhanced prediction of safe return to work.

The neural basis of impulsive discounting in pathological gamblers

Abstract: Pathological gambling is thought to result from a shift of balance between two competing neurobiological mechanisms: on the one hand the reward system involved in the regulation of the urge to get rewards and on the other hand the top-down control system. Fifteen pathological gamblers (PG) and fifteen healthy controls (HC) were studied in an event-related functional magnetic resonance imaging experiment where participants had to choose either a smaller, but immediately available monetary reward (SIR) or a larger delayed reward (LDR). We examined contrasts between LDR and SIR decisions. Additionally, we contrasted choices near the individual indifference point (indifferent decisions) and clear SIR or LDR choices (sure decisions). Behavioral data confirmed former results of steeper discount rates in PG. Contrasting choices of LDR vs. SIR showed widespread bilateral activations in PG, including postcentral gyrus, thalamus, superior/medial frontal gyrus and cingulate gyrus, whereas HC demonstrated only focal left-sided pre/postcentral activity. Forgoing an immediate reward thus recruits a widespread brain network including typical control areas. Indifferent vs. sure decisions were associated with widespread activation in PG, including the bilateral fronto-parietal cortex, insula, anterior cingulate gyrus, and striatum, whereas in HC, only bilateral frontal cortex and insula were activated. The reverse contrast demonstrated more activity for sure decisions in the cingulate gyrus, insula, and medial frontal gyrus in HC, whereas PG showed inferior parietal and superior temporal activity. The present study demonstrates that pathological gambling is associated with a shift in the interplay between a prefrontal-parietal control network and a brain network involved in immediate reward consumption.

Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population

Abstract: PTSD and TBI are two common conditions in veteran populations that can be difficult to distinguish clinically. The default mode network (DMN) is abnormal in a multitude of neurological and psychiatric disorders. We hypothesize that brain perfusion SPECT can be applied to diagnostically separate PTSD from TBI reliably in a veteran cohort using DMN regions. A group of 196 veterans (36 with PTSD, 115 with TBI, 45 with PTSD/TBI) were selected from a large multi-site population cohort of individuals with psychiatric disease. Inclusion criteria were peacetime or wartime veterans regardless of branch of service and included those for whom the traumatic brain injury was not service related. SPECT imaging was performed on this group both at rest and during a concentration task. These measures, as well as the baseline-concentration difference, were then inputted from DMN regions into separate binary logistic regression models controlling for age, gender, race, clinic site, co-morbid psychiatric diseases, TBI severity, whether or not the TBI was service related, and branch of armed service. Predicted probabilities were then inputted into a receiver operating characteristic analysis to compute sensitivity, specificity, and accuracy. Compared to PSTD, persons with TBI were older, male, and had higher rates of bipolar and major depressive disorder (p < 0.05). Baseline quantitative regions with SPECT separated PTSD from TBI in the veterans with 92 % sensitivity, 85 % specificity, and 94 % accuracy. With concentration scans, there was 85 % sensitivity, 83 % specificity and 89 % accuracy. Baseline-concentration (the difference metric between the two scans) scans were 85 % sensitivity, 80 % specificity, and 87 % accuracy. In separating TBI from PTSD/TBI visual readings of baseline scans had 85 % sensitivity, 81 % specificity, and 83 % accuracy. Concentration scans had 80 % sensitivity, 65 % specificity, and 79 % accuracy. Baseline-concentration scans had 82 % sensitivity, 69 % specificity, and 81 % accuracy. For separating PTSD from PTSD/TBI baseline scans had 87 % sensitivity, 83 % specificity, and 92 % accuracy. Concentration scans had 91 % sensitivity, 76 % specificity, and 88 % accuracy. Baseline-concentration scans had 84 % sensitivity, 64 % specificity, and 85 % accuracy. This study demonstrates the ability to separate PTSD and TBI from each other in a veteran population using functional neuroimaging.

Right is not always wrong: DTI and fMRI evidence for the reliance of reading comprehension on language-comprehension networks in the right hemisphere

Abstract: The Simple View theory suggests that reading comprehension relies on automatic recognition of words combined with language comprehension. The goal of the current study was to examine the structural and functional connectivity in networks supporting reading comprehension and their relationship with language comprehension within 7-9 year old children using Diffusion Tensor Imaging (DTI) and fMRI during a Sentence Picture Matching task. Fractional Anisotropy (FA) values in the left and right Inferior Longitudinal Fasciculus (ILF) and Superior Longitudinal Fasciculus (SLF), known language-related tracts, were correlated from DTI data with scores from the Woodcock-Johnson III (WJ-III) Passage Comprehension sub-test. Brodmann areas most proximal to white-matter regions with significant correlation to Passage Comprehension scores were chosen as Regions-of-Interest (ROIs) and used as seeds in a functional connectivity analysis using the Sentence Picture Matching task. The correlation between percentile scores for the WJ-III Passage Comprehension subtest and the FA values in the right and left ILF and SLF indicated positive correlation in language-related ROIs, with greater distribution in the right hemisphere, which in turn showed strong connectivity in the fMRI data from the Sentence Picture Matching task. These results support the participation of the right hemisphere in reading comprehension and may provide physiologic support for a distinction between different types of reading comprehension deficits vs difficulties in technical reading.

Statistical estimation of physiological brain age as a descriptor of senescence rate during adulthood

Abstract: Mapping aging-related brain structure and connectivity changes can be helpful for assessing physiological brain age (PBA), which is distinct from chronological age (CA) because genetic and environmental factors affect individuals differently. This study proposes an approach whereby structural and connectomic information can be combined to estimate PBA as an early biomarker of brain aging. In a cohort of 136 healthy adults, magnetic resonance and diffusion tensor imaging are respectively used to measure cortical thickness over the entire cortical mantle as well as connectivity properties (mean connectivity density and mean fractional anisotropy) for white matter connections. Using multivariate regression, these measurements are then employed to (1) illustrate how CA can be predicated--and thereby also how PBA can be estimated--and to conclude that (2) healthy aging is associated with significant connectome changes during adulthood. Our study illustrates a connectomically-informed statistical approach to PBA estimation, with potential applicability to the clinical identification of patients who exhibit accelerated brain aging, and who are consequently at higher risk for developing mild cognitive impairment or dementia.

Who wants a free brain scan? Assessing and correcting for recruitment biases in a population-based sMRI pilot study

Abstract: Neuroimaging research is usually conducted in volunteers who meet a priori selection criteria. Selection/volunteer bias is assumed but cannot be assessed. During an ongoing population-based cohort study of 1982 older adults, we asked 1702 active participants about their interest in undergoing a research brain scan. Compared with those not interested, the 915 potentially interested individuals were significantly younger, more likely to be male, better educated, generally healthier, and more likely to be cognitively intact and dementia-free. In 48 of the interested individuals, we conducted a previously reported pilot structural magnetic resonance imaging (sMRI) study modelling mild cognitive impairment (MCI) vs. normal cognition, and Clinical Dementia Rating (CDR) = 0.5 vs. CDR = 0, as a function of sMRI atrophy ratings. We now compare these 48 individuals (1) with all interested participants, to assess selection bias; (2) with all who had been asked about their interest, to assess volunteer bias; and (3) with the entire study cohort, to assess attrition bias from those who had dropped out before the question was asked. Using these data in propensity score models, we generated weights which we applied to logistic regression models reanalyzing the data from the pilot sMRI study. These weighted models adjusted, in turn, for selection bias, interest/volunteer bias, and attrition bias. They show fewer regions of interest to be associated with MCI/ CDR than were in the original unweighted models. When study participants are drawn from a well-characterized population, they can be compared with non-participants, and the information used to correct study results for potential bias and thus provide more generalizable estimates.

Subgroups of US IRAQ and Afghanistan veterans: associations with traumatic brain injury and mental health conditions

Abstract: U. S. veterans of Iraq and Afghanistan are known to have a high prevalence of traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and depression, which are often comorbid and share many symptoms. Attempts to describe this cohort by single diagnoses have limited our understanding of the complex nature of this population. The objective of this study was to identify subgroups of Iraq and Afghanistan veterans (IAVs) with distinct compositions of symptoms associated with TBI, PTSD, and depression. Our cross-sectional, observational study included 303,716 IAVs who received care in the Veterans Health Administration in 2010–2011. Symptoms and conditions were defined using International Classification of Diseases, Ninth Revision codes and symptom-clusters were identified using latent class analysis. We identified seven classes with distinct symptom compositions. One class had low probability of any condition and low health care utilization (HCU) (48 %). Other classes were characterized by high probabilities of mental health comorbidities (14 %); chronic pain and sleep disturbance (20 %); headaches and memory problems (6 %); and auditory problems (2.5 %). Another class had mental health comorbidities and chronic pain (7 %), and the last had high probabilities of most symptoms examined (3 %). These last two classes had the highest likelihood of TBI, PTSD, and depression and were identified as high healthcare utilizers. There are subgroups of IAVs with distinct clusters of symptom that are meaningfully associated with TBI, PTSD, depression, and HCU. Additional studies examining these veteran subgroups could improve our understanding of this complex comorbid patient population.

Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson’s disease

Abstract: Parkinson’s disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG–cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen–medial parietal and pallidum–occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate–supramarginal gyrus and pallidum–inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal–cortical connectivity, specifically between caudate–prefrontal, caudate–precuneus, and putamen–motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.

Functional-structural degeneration in dorsal and ventral attention systems for Alzheimer’s disease, amnestic mild cognitive impairment

Abstract: Growing evidence of attention related failures in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) has already been proposed by previous studies However, previous studies lacked of systematic investigation on the functional and structural substrates for attention function for patients with AD and aMCI In this work, we investigated the functional connectivity and gray matter density in dorsal and ventral attention networks (DAN, VAN) of normal participants (n = 15) and patients with aMCI (n = 12) and AD (n = 16) by applying group independent component analysis (ICA) and voxel-based morphometry (VBM) analysis Using ICA, we extracted the functional patterns of DAN and VAN which are respectively responsible for the “top-down” attention process and “bottom-up” process One-way analysis of variance (ANOVA) revealed significant group-differed functional connectivity in bilateral frontal eye fields (FEF) area and intraparietal sulcus (IPS) area, as well as posterior cingulate cortex and precuneus in the dorsal system With regard to the ventral system, group-effects were significantly focused in right orbital superior/middle frontal gyrus, right inferior parietal lobule, angular gyrus, and supramarginal gyrus around the temporal-parietal junction area Post hoc cluster-level comparisons revealed totally impaired functional substrates for both attentional networks for patients with AD, whereas selectively impaired attention systems for patients with aMCI with impaired functional patent of DAN but preserved functional pattern of VAN Correspondingly, VBM analysis revealed gray matter loss in right ventral and dorsal frontal cortex was in the AD group, whereas preserved gray matter density was in aMCI, even a little extent of expansion of gray matter density in several participants Using multivariate regression analysis we found discrepant couplings of functional-structural degenerations between both patient groups Specifically, positive coupling of structural-functional degeneration was found in right dorsal and ventral frontal cortex in the AD group, whereas inverse coupling in dorsal frontal cortex was found in the aMCI group These findings suggested discrepant functional-structural degenerations in both attention systems between both patient groups, widening avenues to better understanding the attentional deficits in patients with aMCI and AD

Effects of reaction time variability and age on brain activity during Stroop task performance

Abstract: Variability in reaction time during task performance may reflect fluctuations in attention and cause reduced performance in goal-directed tasks, yet it is unclear whether the mechanisms behind this phenomenon change with age. Using fMRI, we tested young and cognitively healthy older adults with the Stroop task to determine whether aging affects the neural mechanisms underlying intra-individual reaction time variability. We found significant between-group differences in BOLD activity modulated by reaction time. In older adults, longer reaction times were associated with greater activity in frontoparietal attentional areas, while in younger adults longer reaction times were associated with greater activity in default mode network areas. Our results suggest that the neural correlates of reaction time variability change with healthy aging, reinforcing the concept of functional plasticity to maintain high cognitive function throughout the lifespan.

The neural basis of attaining conscious awareness of sad mood

Abstract: The neural processes associated with becoming aware of sad mood are not fully understood. We examined the dynamic process of becoming aware of sad mood and recovery from sad mood. Sixteen healthy subjects underwent fMRI while participating in a sadness induction task designed to allow for variable mood induction times. Individualized regressors linearly modeled the time periods during the attainment of self-reported sad and baseline "neutral" mood states, and the validity of the linearity assumption was further tested using independent component analysis. During sadness induction the dorsomedial and ventrolateral prefrontal cortices, and anterior insula exhibited a linear increase in the blood oxygen level-dependent (BOLD) signal until subjects became aware of a sad mood and then a subsequent linear decrease as subjects transitioned from sadness back to the non-sadness baseline condition. These findings extend understanding of the neural basis of conscious emotional experience.

Fiber bundle length and cognition: a length-based tractography MRI study

Abstract: Executive function (EF) and cognitive processing speed (CPS) are two cognitive performance domains that decline with advanced age. Reduced EF and CPS are known to correlate with age-related frontal-lobe volume loss. However, it remains unclear whether white matter microstructure in these regions is associated with age-related decline in EF and/or CPS. We utilized quantitative tractography metrics derived from diffusion-tensor MRI to investigate the relationship between the mean fiber bundle lengths (FBLs) projecting to different lobes, and EF/CPS performance in 73 healthy aging adults. We measured aspects of EF and CPS with the Trail Making Test (TMT), Color-Word Interference Test, Letter-Number Sequencing (L-N Seq), and Symbol Coding. Results revealed that parietal and occipital FBLs explained a significant portion of variance in EF. Frontal, temporal, and occipital FBLs explained a significant portion of variance in CPS. Shorter occipital FBLs were associated with poorer performance on the EF tests TMT-B and CWIT 3. Shorter frontal, parietal, and occipital FBLs were associated with poorer performance on L-N Seq and Symbol Coding. Shorter frontal and temporal FBLs were associated with lower performance on CPS tests TMT-A and CWIT 1. Shorter FBLs were also associated with increased age. Results suggest an age-related FBL shortening in specific brain regions related to poorer EF and CPS performance among older adults. Overall, results support both the frontal aging hypothesis and processing speed theory, suggesting that each mechanism is contributing to age-related cognitive decline.