Andrew R. Mayer

A Baseline for the Multivariate Comparison of Resting-State Networks

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12–71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease.

A prospective diffusion tensor imaging study in mild traumatic brain injury

Objectives: Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls. Methods: Twenty-two patients with semi-acute mTBI (mean = 12 days postinjury), 21 matched healthy controls, and a larger sample (n = 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3–5 months after their initial visit. Results: mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts. Conclusions: Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.

Functional connectivity in mild traumatic brain injury

Objectives: Research suggests that the majority of mild traumatic brain injury (mTBI) patients exhibit both cognitive and emotional dysfunction within the first weeks of injury, followed by symptom resolution 3–6 months postinjury. The neuronal correlates of said dysfunction are difficult to detect with standard clinical neuroimaging, complicating differential diagnosis and early identification of patients who may not recover. This study examined whether resting state functional magnetic resonance imaging (fMRI) provides objective markers of injury and predicts cognitive, emotional, and somatic complaints in mTBI patients semiacutely (<3 weeks postinjury) and in late recovery (3–5 month) phases. Methods: Twenty‐seven semiacute mTBI patients and 26 gender, age, and education‐matched controls were studied. Fifteen of 27 patients returned for a follow‐up visit 3–5 months postinjury. The main dependent variables were spontaneous fluctuations (temporal correlation) in the default‐mode (DMN) and fronto‐parietal task‐related networks as measured by fMRI. Results: Significant differences in self‐reported cognitive, emotional, and somatic complaints were observed (all P < 0.05), despite normal clinical (T1 and T2) imaging and neuropsychological testing results. Mild TBI patients demonstrated decreased functional connectivity within the DMN and hyper‐connectivity between the DMN and lateral prefrontal cortex. Measures of functional connectivity exhibited high levels of sensitivity and specificity for patient classification and predicted cognitive complaints in the semi‐acute injury stage. However, no changes in functional connectivity were observed across a 4‐month recovery period. Conclusions: Abnormal connectivity between the DMN and frontal cortex may provide objective biomarkers of mTBI and underlie cognitive impairment. Hum Brain Mapp, 2011.

Motor Sequence Complexity and Performing Hand Produce Differential Patterns of Hemispheric Lateralization

Studies in brain damaged patients conclude that the left hemisphere is dominant for controlling heterogeneous sequences performed by either hand, presumably due to the cognitive resources involved in planning complex sequential movements. To determine if this lateralized effect is due to asymmetries in primary sensorimotor or association cortex, whole-brain functional magnetic resonance imaging was used to measure differences in volume of activation while healthy right-handed subjects performed repetitive (simple) or heterogeneous (complex) finger sequences using the right or left hand. Advanced planning, as evidenced by reaction time to the first key press, was greater for the complex than simple sequences and for the left than right hand. In addition to the expected greater contralateral activation in the sensorimotor cortex (SMC), greater left hemisphere activation was observed for left, relative to right, hand movements in the ipsilateral left superior parietal area and for complex, relative to simple, sequences in the left premotor and parietal cortex, left thalamus, and bilateral cerebellum. No such volumetric asymmetries were observed in the SMC. Whereas the overall MR signal intensity was greater in the left than right SMC, the extent of this asymmetry did not vary with hand or complexity level. In contrast, signal intensity in the parietal and premotor cortex was greater in the left than right hemisphere and for the complex than simple sequences. Signal intensity in the caudal anterior cerebellum was greater bilaterally for the complex than simple sequences. These findings suggest that activity in the SMC is associated with execution requirements shared by the simple and complex sequences independent of their differential cognitive requirements. In contrast, consistent with data in brain damaged patients, the left dorsal premotor and parietal areas are engaged when advanced planning is required to perform complex motor sequences that require selection of different effectors and abstract organization of the sequence, regardless of the performing hand.

A Longitudinal Proton Magnetic Resonance Spectroscopy Study of Mild Traumatic Brain Injury

Despite the prevalence and impact of mild traumatic brain injury (mTBI), common clinical assessment methods for mTBI have insufficient sensitivity and specificity. Moreover, few researchers have attempted to document underlying changes in physiology as a function of recovery from mTBI. Proton magnetic resonance spectroscopy (¹H-MRS) was used to assess neurometabolite concentrations in a supraventricular tissue slab in 30 individuals with semi-acute mTBI, and 30 sex-, age-, and education-matched controls. No significant group differences were evident on traditional measures of attention, memory, working memory, processing speed, and executive skills, though the mTBI group reported significantly more somatic, cognitive, and emotional symptoms. At a mean of 13 days post-injury, white matter concentrations of creatine (Cre) and phosphocreatine (PCre) and the combined glutamate-glutamine signal (Glx) were elevated in the mTBI group, while gray matter concentrations of Glx were reduced. Partial normalization of these three neurometabolites and N-acetyl aspartate occurred in the early days post-injury, during the semi-acute period of recovery. In addition, 17 mTBI patients (57%) returned for a follow-up evaluation (mean = 120 days post-injury). A significant group × time interaction indicated recovery in the mTBI group for gray matter Glx, and trends toward recovery in white matter Cre and Glx. An estimate of premorbid intelligence predicted the magnitude of neurometabolite normalization over the follow-up interval for the mTBI group, indicating that biological factors underlying intelligence may also be associated with more rapid recovery.

Resting state and task-induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls

Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task‐related networks permits the quantification of this network both during task (task‐induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed‐based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed‐based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia. Hum Brain Mapp, 2010.

Biomarkers of increased diffusion anisotropy in semi-acute mild traumatic brain injury: a longitudinal perspective

Mild traumatic brain injury is the most prevalent neurological insult and frequently results in neurobehavioural sequelae. However, little is known about the pathophysiology underlying the injury and how these injuries change as a function of time. Although diffusion tensor imaging holds promise for in vivo characterization of white matter pathology, both the direction and magnitude of anisotropic water diffusion abnormalities in axonal tracts are actively debated. The current study therefore represents both an independent replication effort (n = 28) of our previous findings (n = 22) of increased fractional anisotropy during semi-acute injury, as well as a prospective study (n = 26) on the putative recovery of diffusion abnormalities. Moreover, new analytical strategies were applied to capture spatially heterogeneous white matter injuries, which minimize implicit assumptions of uniform injury across diverse clinical presentations. Results indicate that whereas a general pattern of high anisotropic diffusion/low radial diffusivity was present in various white matter tracts in both the replication and original cohorts, this pattern was only consistently observed in the genu of the corpus callosum across both samples. Evidence for a greater number of localized clusters with increased anisotropic diffusion was identified across both cohorts at trend levels, confirming heterogeneity in white matter injury. Pooled analyses (50 patients; 50 controls) suggested that measures of diffusion within the genu were predictive of patient classification, albeit at very modest levels (71% accuracy). Finally, we observed evidence of recovery in lesion load in returning patients across a 4-month interval, which was correlated with a reduction in self-reported post-concussive symptomatology. In summary, the corpus callosum may serve as a common point of injury in mild traumatic brain injury secondary to anatomical (high frequency of long unmyelinated fibres) and biomechanics factors. A spatially heterogeneous pattern of increased anisotropic diffusion exists in various other white matter tracts, and these white matter anomalies appear to diminish with recovery. This macroscopic pattern of diffusion abnormalities may be associated with cytotoxic oedema following mechanical forces, resulting in changes in ionic homeostasis, and alterations in the ratio of intracellular and extracellular water. Animal models more specific to the types of mild traumatic brain injury typically incurred by humans are needed to confirm the histological correlates of these macroscopic markers of white matter pathology.

An Event-related fMRI Study of Exogenous Orienting: Supporting Evidence for the Cortical Basis of Inhibition of Return?

This event-related fMRI experiment examined the neural substrates of exogenous visuospatial attention. Exogenous attention produces a biphasic response pattern denoted by facilitation at short cuetarget intervals and inhibition of return (IOR) at longer intervals. Whereas the volitional orienting of attention has been well described in the literature, the neural systems that support exogenous facilitation and IOR in humans are relatively unknown. In direct comparisons to valid facilitation trials, valid IOR trials produced unique foci of activation in the right posterior parietal, superior temporal, middle temporal, middle occipital, anterior cingulate, and dorsal medial thalamic areas. Valid IOR trials also resulted in activation of motor exploratory and frontal areas previously associated with inhibition and oculomotor control. In contrast, invalid IOR compared to facilitation trials only activated anterior cortical structures. These results provide support for both attentional and oculomotor theories of IOR and suggest that IOR may be mediated by two networks. One network may mediate the inhibitory bias following an exogenous cue, whereas a separate network may be activated when a response must be made to stimuli that appear in inhibited locations of space.

Enhanced Cue Reactivity and Fronto-striatal Functional Connectivity in Cocaine Use Disorders

Chronic cocaine use is associated with enhanced cue reactivity to drug stimuli. However, it may also alter functional connectivity (fcMRI) in regions involved in processing drug stimuli. Our aims were to evaluate the neural regions involved in subjective craving and how fcMRI may be altered in chronic cocaine users. Fourteen patients with a confirmed diagnosis of cocaine abuse or dependence (CCA) and 16 gender, age, and education-matched healthy controls (HC) completed a cue reactivity task and a resting state scan while undergoing functional magnetic resonance imaging. CCA showed increased activation compared to HC in left dorsolateral prefrontal and bilateral occipital cortex in response to cocaine cues but not to appetitive control stimuli. Moreover, CCA also showed increased activation within the orbital frontal cortex (OFC) for cocaine cues relative to the appetitive stimuli during a hierarchical regression analysis. A negative association between subjective craving and activity in medial posterior cingulate gyrus (PCC) was also observed for CCA. CCA exhibited increased resting state correlation (positive) between cue-processing seed regions (OFC and ventral striatum), and negative connectivity between cue-processing regions and PCC/precuneus. These alterations in fcMRI may partially explain the neural basis of increased drug cue salience in CCA.

Interrater and intermethod reliability of default mode network selection

There has been a growing interest in the neuroimaging community regarding resting state data (i.e., passive mental activity) and the subsequent activation of the so‐called default mode network (DMN). Although this network was originally characterized by a pattern of deactivation during active cognitive states, more recent applications of data‐driven techniques such as independent component analysis (ICA) have permitted the analysis of brain activation during extended periods of truly passive mental activity. However, ICA requires the resultant components to be evaluated for “goodness of fit” via either human raters or more automated techniques. To our knowledge, an investigation on the reliability of either technique in determining the component that best corresponds to default‐mode activity has not been performed. Moreover, it is not clear how automated techniques, which are necessarily dependent upon a template mask, are affected by the structures used to compose the mask. The current study investigated both interrater (human‐human) reliability and intermethod (human‐machine) reliability for determining DMN activation in 42 healthy controls. Results indicated that near perfect interrater reliability was achieved, whereas intermethod reliability was only within the moderate range. The latter was significantly improved via a weighted combination of the anterior and posterior cingulate nodes of the DMN. Implications for fully automating the component selection process are discussed. Hum Brain Mapp, 2009.