Josef M. Ling

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.

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.

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.

Head Injury or Head Motion? Assessment and Quantification of Motion Artifacts in Diffusion Tensor Imaging Studies

The relationship between head motion and diffusion values such as fractional anisotropy (FA) and mean diffusivity (MD) is currently not well understood. Simulation studies suggest that head motion may introduce either a positive or negative bias, but this has not been quantified in clinical studies. Moreover, alternative measures for removing bias as result of head motion, such as the removal of problematic gradients, has been suggested but not carefully evaluated. The current study examined the impact of head motion on FA and MD across three common pipelines (tract‐based spatial statistics, voxelwise, and region of interest analyses) and determined the impact of removing diffusion weighted images. Our findings from a large cohort of healthy controls indicate that while head motion was associated with a positive bias for both FA and MD, the effect was greater for MD. The positive bias was observed across all three analysis pipelines and was present following established protocols for data processing, suggesting that current techniques (i.e., correction of both image and gradient table) for removing motion bias are likely insufficient. However, the removal of images with gross artifacts did not fundamentally change the relationship between motion and DTI scalar values. In addition, Monte Carlo simulations suggested that the random removal of images increases the bias and reduces the precision of both FA and MD. Finally, we provide an example of how head motion can be quantified across different neuropsychiatric populations, which should be implemented as part of any diffusion tensor imaging quality assurance protocol. Hum Brain Mapp, 2012.

Auditory Orienting and Inhibition of Return in Mild Traumatic Brain Injury: A FMRI Study

The semiacute phase of mild traumatic brain injury (mTBI) is associated with deficits in the cognitive domains of attention, memory, and executive function, which previous work suggests may be related to a specific deficit in disengaging attentional focus. However, to date, there have only been a few studies that have employed dynamic imaging techniques to investigate the potential neurological basis of these cognitive deficits during the semiacute stage of injury. Therefore, event‐related functional magnetic resonance imaging was used to investigate the neurological correlates of attentional dysfunction in a clinically homogeneous sample of 16 patients with mTBI during the semiacute phase of injury (<3 weeks). Behaviorally, patients with mTBI exhibited deficits in disengaging and reorienting auditory attention following invalid cues as well as a failure to inhibit attentional allocation to a cued spatial location compared to a group of matched controls. Accordingly, patients with mTBI also exhibited hypoactivation within thalamus, striatum, midbrain nuclei, and cerebellum across all trials as well as hypoactivation in the right posterior parietal cortex, presupplementary motor area, bilateral frontal eye fields, and right ventrolateral prefrontal cortex during attentional disengagement. Finally, the hemodynamic response within several regions of the attentional network predicted response times better for controls than for patients with mTBI. These objective neurological findings represent a potential biomarker for the behavioral deficits in spatial attention that characterize the initial recovery phase of mTBI. Hum Brain Mapp, 2009.

Diffusion Abnormalities in Pediatric Mild Traumatic Brain Injury

Pediatric mild traumatic brain injury (pmTBI) is the most prevalent neurological insult in children and is associated with both acute and chronic neurobehavioral sequelae. However, little is known about underlying pathophysiology and how injuries change as a function of recovery. Fractional anisotropy, axial diffusivity, and radial diffusivity were examined in 15 semi-acute pmTBI patients and 15 well-matched controls, with a subset of participants returning for a second visit. A novel analytic strategy was applied to capture spatially heterogeneous white matter injuries (lesions) in addition to standard analyses. Evidence of cognitive dysfunction after pmTBI was observed in the domains of attention (p = 0.02, d = −0.92) and processing speed (p = 0.05, d = −0.73) semi-acutely. Region of interest (ROI) and voxelwise analyses indicated increased anisotropic diffusion for pmTBI patients, with an elevated number of clusters with high anisotropy. Metrics of increased anisotropy were able to objectively classify pmTBI from healthy controls at 90% accuracy but were not associated with neuropsychological deficits. Little evidence of recovery in white matter abnormalities was observed over a 4-month interval in returning patients, indicating that physiological recovery may lag behind subjective reports of normality. Increased anisotropic diffusion has been previously linked with cytotoxic edema after TBI, and the magnitude and duration of these abnormalities appear to be greater in pediatric patients. Current findings suggest that developing white matter may be more susceptible to initial mechanical injury forces and that anisotropic diffusion provides an objective biomarker of pmTBI.

A prospective study of gray matter abnormalities in mild traumatic brain injury

Objective: To examine the underlying pathophysiology of mild traumatic brain injury through changes in gray matter diffusion and atrophy during the semiacute stage. Methods: Fifty patients and 50 sex-, age-, and education-matched controls were evaluated with a clinical and neuroimaging battery approximately 14 days postinjury, with 26 patients returning for follow-up 4 months postinjury. Clinical measures included tests of attention, processing speed, executive function, working memory, memory, and self-reported postconcussive symptoms. Measures of diffusion (fractional anisotropy [FA], mean diffusivity) and atrophy were obtained for cortical and subcortical structures to characterize effects of injury as a function of time. Results: Patients reported more cognitive, somatic, and emotional complaints during the semiacute injury phase, which were significantly reduced 4 months postinjury. Patients showed evidence of increased FA in the bilateral superior frontal cortex during the semiacute phase, with the left superior frontal cortex remaining elevated 4 months postinjury. There were no significant differences between patients and matched controls on neuropsychological testing or measures of gray matter atrophy/mean diffusivity at either time point. Conclusions: Increased cortical FA is largely consistent with an emerging animal literature of gray matter abnormalities after neuronal injury. Potential mechanistic explanations for increased FA include cytotoxic edema or reactive gliosis. In contrast, there was no evidence of cortical or subcortical atrophy in the current study, suggesting that frank neuronal or neuropil loss does not occur early in the chronic disease course for patients with typical mild traumatic brain injury.

Functional Imaging of the Hemodynamic Sensory Gating Response in Schizophrenia

The cortical (auditory and prefrontal) and/or subcortical (thalamic and hippocampal) generators of abnormal electrophysiological responses during sensory gating remain actively debated in the schizophrenia literature. Functional magnetic resonance imaging has the spatial resolution for disambiguating deep or simultaneous sources but has been relatively under‐utilized to investigate generators of the gating response. Thirty patients with chronic schizophrenia (SP) and 30 matched controls participated in the current experiment. Hemodynamic response functions (HRFs) for single (S1) and pairs (S1 + S2) of identical (“gating‐out” redundant information) or nonidentical (“gating‐in” novel information) tones were generated through deconvolution. Increased or prolonged activation for patients in conjunction with deactivation for controls was observed within auditory cortex, prefrontal cortex, and thalamus in response to single tones during the late hemodynamic response, and these group differences were not associated with clinical or cognitive symptomatology. Although patient hyperactivation to paired‐tones conditions was present in several regions of interest, the effects were not statistically significant for either the gating‐out or gating‐in conditions. Finally, abnormalities in the postundershoot of the auditory HRF were also observed for both single and paired‐tones conditions in patients. In conclusion, the amalgamation of the entire electrophysiological response to both S1 and S2 stimuli may limit hemodynamic sensitivity to paired tones during sensory gating, which may be more readily overcome by paradigms that use multiple stimuli rather than pairs. Patient hyperactivation following single tones is suggestive of deficits in basic inhibition, neurovascular abnormalities, or a combination of both factors. Hum Brain Mapp 34:2302–2312, 2013.

Modeling conflict and error in the medial frontal cortex.

Despite intensive study, the role of the dorsal medial frontal cortex (dMFC) in error monitoring and conflict processing remains actively debated. The current experiment manipulated conflict type (stimulus conflict only or stimulus and response selection conflict) and utilized a novel modeling approach to isolate error and conflict variance during a multimodal numeric Stroop task. Specifically, hemodynamic response functions resulting from two statistical models that either included or isolated variance arising from relatively few error trials were directly contrasted. Twenty‐four participants completed the task while undergoing event‐related functional magnetic resonance imaging on a 1.5‐Tesla scanner. Response times monotonically increased based on the presence of pure stimulus or stimulus and response selection conflict. Functional results indicated that dMFC activity was present during trials requiring response selection and inhibition of competing motor responses, but absent during trials involving pure stimulus conflict. A comparison of the different statistical models suggested that relatively few error trials contributed to a disproportionate amount of variance (i.e., activity) throughout the dMFC, but particularly within the rostral anterior cingulate gyrus (rACC). Finally, functional connectivity analyses indicated that an empirically derived seed in the dorsal ACC/pre‐SMA exhibited strong connectivity (i.e., positive correlation) with prefrontal and inferior parietal cortex but was anti‐correlated with the default‐mode network. An empirically derived seed from the rACC exhibited the opposite pattern, suggesting that sub‐regions of the dMFC exhibit different connectivity patterns with other large scale networks implicated in internal mentations such as daydreaming (default‐mode) versus the execution of top‐down attentional control (fronto‐parietal). Hum Brain Mapp, 2012.

Static and Dynamic Intrinsic Connectivity following Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the most common neurological disorder and is typically characterized by temporally limited cognitive impairment and emotional symptoms. Previous examinations of intrinsic resting state networks in mTBI have primarily focused on abnormalities in static functional connectivity, and deficits in dynamic functional connectivity have yet to be explored in this population. Resting-state data was collected on 48 semi-acute (mean = 14 days post-injury) mTBI patients and 48 matched healthy controls. A high-dimensional independent component analysis (N = 100) was utilized to parcellate intrinsic connectivity networks (ICN), with a priori hypotheses focusing on the default-mode network (DMN) and sub-cortical structures. Dynamic connectivity was characterized using a sliding window approach over 126 temporal epochs, with standard deviation serving as the primary outcome measure. Finally, distribution-corrected z-scores (DisCo-Z) were calculated to investigate changes in connectivity in a spatially invariant manner on a per-subject basis. Following appropriate correction for multiple comparisons, no significant group differences were evident on measures of static or dynamic connectivity within a priori ICN. Reduced (HC > mTBI patients) static connectivity was observed in the DMN at uncorrected (p < 0.005) thresholds. Finally, a trend (p = 0.07) for decreased dynamic connectivity in patients across all ICN was observed during spatially invariant analyses (DisCo-Z). In the semi-acute phase of recovery, mTBI was not reliably associated with abnormalities in static or dynamic functional connectivity within the DMN or sub-cortical structures.