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.

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.

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.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.

Impact of analysis methods on the reproducibility and reliability of resting-state networks.

Though previous examinations of intrinsic resting-state networks (RSNs) in healthy populations have consistently identified several RSNs that represent connectivity patterns evoked by cognitive and sensory tasks, the effects of different analytic approaches on the reliability and reproducibility of these RSNs have yet to be fully explored. Thus, the primary aim of the current study was to investigate the effect of method (independent component analyses [ICA] vs. seed-based analyses) on RSN reproducibility (independent datasets) for ICA and reliability (independent time points) in both methods using functional magnetic resonance imaging. Good to excellent reproducibility was observed in 9 out of 10 commonly identified RSNs, indicating the robustness of these intrinsic fluctuations at the group level. Reliability analyses showed that results were dependent on three main methodological factors: (1) group versus subject-level analyses (group>subject); (2) whether data from different visits were analyzed separately or jointly with ICA (combined>separate ICA); and (3) whether ICA output was used to directly assess reliability or to inform seed-based analyses (seed-based>ICA). These results suggest that variations in the analytic technique have a significant impact on individual reliability measurements, but do not significantly affect the reproducibility or reliability of RSNs at the group level. Further investigation into the effect of the analytic technique on RSN quantification is warranted to increase the utility of RSN analyses in clinical studies.

A functional MRI study of multimodal selective attention following mild traumatic brain injury.

Previous work suggests that the ability to selectively attend to and resolve conflicting information may be the most enduring cognitive deficit following mild traumatic brain injury (mTBI). The current study used fMRI to evaluate potential differences in hemodynamic activation in 22 mTBI patients and 22 carefully matched healthy controls (HC) during a multimodal selective attention task (numeric Stroop). Behavioral data indicated faster reaction times for congruent versus incongruent trials and for stimuli presented at 0.66 compared to 0.33 Hz across both groups, with minimal differences in behavioral performance across the groups. Similarly, there were no group-wise differences in functional activation within lateral and medial prefrontal cortex during the execution of cognitive control (incongruent versus congruent trials). In contrast, within-group comparisons indicated robust patterns of attention-related modulations (ARM) within the bilateral dorsolateral prefrontal cortex and bilateral visual streams for HC but not mTBI patients. In addition, mTBI patients failed to exhibit task-induced deactivation within the default-mode network (DMN) under conditions of higher attentional load. In summary, in spite of near normal behavioral performance, current results suggest within-group abnormalities during both the top-down allocation of visual attention and in regulating the DMN during the semi-acute stage of mTBI.