Evan S. Lutkenhoff

Developmental disruptions in neural connectivity in the pathophysiology of schizophrenia.

Schizophrenia has been thought of as a disorder of reduced functional and structural connectivity. Recent advances in neuroimaging techniques such as functional magnetic resonance imaging, structural magnetic resonance imaging, diffusion tensor imaging, and small animal imaging have advanced our ability to investigate this hypothesis. Moreover, the power of longitudinal designs possible with these noninvasive techniques enable the study of not just how connectivity is disrupted in schizophrenia, but when this disruption emerges during development. This article reviews genetic and neurodevelopmental influences on structural and functional connectivity in human populations with or at risk for schizophrenia and in animal models of the disorder. We conclude that the weight of evidence across these diverse lines of inquiry points to a developmental disruption of neural connectivity in schizophrenia and that this disrupted connectivity likely involves susceptibility genes that affect processes involved in establishing intra- and interregional connectivity.

Proton MRS in twin pairs discordant for schizophrenia

Proton magnetic resonance spectroscopy (1H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that 1H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.

Dynamic Change of Global and Local Information Processing in Propofol-Induced Loss and Recovery of Consciousness

Whether unique to humans or not, consciousness is a central aspect of our experience of the world. The neural fingerprint of this experience, however, remains one of the least understood aspects of the human brain. In this paper we employ graph-theoretic measures and support vector machine classification to assess, in 12 healthy volunteers, the dynamic reconfiguration of functional connectivity during wakefulness, propofol-induced sedation and loss of consciousness, and the recovery of wakefulness. Our main findings, based on resting-state fMRI, are three-fold. First, we find that propofol-induced anesthesia does not bear differently on long-range versus short-range connections. Second, our multi-stage design dissociated an initial phase of thalamo-cortical and cortico-cortical hyperconnectivity, present during sedation, from a phase of cortico-cortical hypoconnectivity, apparent during loss of consciousness. Finally, we show that while clustering is increased during loss of consciousness, as recently suggested, it also remains significantly elevated during wakefulness recovery. Conversely, the characteristic path length of brain networks (i.e., the average functional distance between any two regions of the brain) appears significantly increased only during loss of consciousness, marking a decrease of global information-processing efficiency uniquely associated with unconsciousness. These findings suggest that propofol-induced loss of consciousness is mainly tied to cortico-cortical and not thalamo-cortical mechanisms, and that decreased efficiency of information flow is the main feature differentiating the conscious from the unconscious brain.

Optimized brain extraction for pathological brains (optiBET).

The study of structural and functional magnetic resonance imaging data has greatly benefitted from the development of sophisticated and efficient algorithms aimed at automating and optimizing the analysis of brain data. We address, in the context of the segmentation of brain from non-brain tissue (i.e., brain extraction, also known as skull-stripping), the tension between the increased theoretical and clinical interest in patient data, and the difficulty of conventional algorithms to function optimally in the presence of gross brain pathology. Indeed, because of the reliance of many algorithms on priors derived from healthy volunteers, images with gross pathology can severely affect their ability to correctly trace the boundaries between brain and non-brain tissue, potentially biasing subsequent analysis. We describe and make available an optimized brain extraction script for the pathological brain (optiBET) robust to the presence of pathology. Rather than attempting to trace the boundary between tissues, optiBET performs brain extraction by (i) calculating an initial approximate brain extraction; (ii) employing linear and non-linear registration to project the approximate extraction into the MNI template space; (iii) back-projecting a standard brain-only mask from template space to the subject’s original space; and (iv) employing the back-projected brain-only mask to mask-out non-brain tissue. The script results in up to 94% improvement of the quality of extractions over those obtained with conventional software across a large set of severely pathological brains. Since optiBET makes use of freely available algorithms included in FSL, it should be readily employable by anyone having access to such tools.

Thalamic and extrathalamic mechanisms of consciousness after severe brain injury.

What mechanisms underlie the loss and recovery of consciousness after severe brain injury? We sought to establish, in the largest cohort of patients with disorders of consciousness (DOC) to date, the link between gold standard clinical measures of awareness and wakefulness, and specific patterns of local brain pathology—thereby possibly providing a mechanistic framework for patient diagnosis, prognosis, and treatment development.

Thalamic atrophy in antero-medial and dorsal nuclei correlates with six-month outcome after severe brain injury.

The primary and secondary damage to neural tissue inflicted by traumatic brain injury is a leading cause of death and disability. The secondary processes, in particular, are of great clinical interest because of their potential susceptibility to intervention. We address the dynamics of tissue degeneration in cortico-subcortical circuits after severe brain injury by assessing volume change in individual thalamic nuclei over the first six-months post-injury in a sample of 25 moderate to severe traumatic brain injury patients. Using tensor-based morphometry, we observed significant localized thalamic atrophy over the six-month period in antero-dorsal limbic nuclei as well as in medio-dorsal association nuclei. Importantly, the degree of atrophy in these nuclei was predictive, even after controlling for full-brain volume change, of behavioral outcome at six-months post-injury. Furthermore, employing a data-driven decision tree model, we found that physiological measures, namely the extent of atrophy in the anterior thalamic nucleus, were the most predictive variables of whether patients had regained consciousness by six-months, followed by behavioral measures. Overall, these findings suggest that the secondary non-mechanical degenerative processes triggered by severe brain injury are still ongoing after the first week post-trauma and target specifically antero-medial and dorsal thalamic nuclei. This result therefore offers a potential window of intervention, and a specific target region, in agreement with the view that specific cortico-thalamo-cortical circuits are crucial to the maintenance of large-scale network neural activity and thereby the restoration of cognitive function after severe brain injury.

Alterations in White Matter Microstructure in Neurofibromatosis-1

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well–characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.

Structural and functional neuroimaging phenotypes in dysbindin mutant mice.

Schizophrenia is a highly heritable psychiatric disorder that is associated with a number of structural and functional neurophenotypes. DTNBP1, the gene encoding dysbindin-1, is a promising candidate gene for schizophrenia. Use of a mouse model carrying a large genomic deletion exclusively within the dysbindin gene permits a direct investigation of the gene in isolation. Here, we use manganese-enhanced magnetic resonance imaging (MEMRI) to explore the regional alterations in brain structure and function caused by loss of the gene encoding dysbindin-1. We report novel findings that uniquely inform our understanding of the relationship of dysbindin-1 to known schizophrenia phenotypes. First, in mutant mice, analysis of the rate of manganese uptake into the brain over a 24-hour period, putatively indexing basal cellular activity, revealed differences in dopamine rich brain regions, as well as in CA1 and dentate subregions of the hippocampus formation. Finally, novel tensor-based morphometry techniques were applied to the mouse MRI data, providing evidence for structural volume deficits in cortical regions, subiculum and dentate gyrus, and the striatum of dysbindin mutant mice. The affected cortical regions were primarily localized to the sensory cortices in particular the auditory cortex. This work represents the first application of manganese-enhanced small animal imaging to a mouse model of schizophrenia endophenotypes, and a novel combination of functional and structural measures. It revealed both hypothesized and novel structural and functional neural alterations related to dysbindin-1.

Testing Proposed Neuronal Models of Effective Connectivity Within the Cortico-basal Ganglia-thalamo-cortical Loop During Loss of Consciousness

Abstract In recent years, a number of brain regions and connectivity patterns have been proposed to be crucial for loss and recovery of consciousness but have not been compared in detail. In a 3 T resting‐state functional magnetic resonance imaging paradigm, we test the plausibility of these different neuronal models derived from theoretical and empirical knowledge. Specifically, we assess the fit of each model to the dynamic change in effective connectivity between specific cortical and subcortical regions at different consecutive levels of propofol‐induced sedation by employing spectral dynamic causal modeling. Surprisingly, our findings indicate that proposed models of impaired consciousness do not fit the observed patterns of effective connectivity. Rather, the data show that loss of consciousness, at least in the context of propofol‐induced sedation, is marked by a breakdown of corticopetal projections from the globus pallidus. Effective connectivity between the globus pallidus and the ventral posterior cingulate cortex, present during wakefulness, fades in the transition from lightly sedated to full loss of consciousness and returns gradually as consciousness recovers, thereby, demonstrating the dynamic shift in brain architecture of the posterior cingulate “hub” during changing states of consciousness. These findings highlight the functional role of a previously underappreciated direct pallido‐cortical connectivity in supporting consciousness.

Restoration of thalamo-cortical connectivity after brain injury: recovery of consciousness, complex behavior, or passage of time?

In 2000, a landmark case report described the concurrent restoration of consciousness and thalamo‐frontal connectivity after severe brain injury (Laureys et al., ). Being a single case however, this study could not disambiguate whether the result was specific to the restoration of consciousness per se as opposed to the return of complex cognitive function in general or simply the temporal evolution of post‐injury pathophysiological events. To test whether the restoration of thalamo‐cortical connectivity is specific to consciousness, 20 moderate‐to‐severe brain injury patients (from a recruited sample of 42) underwent resting‐state functional magnetic resonance imaging within a week after injury and again six months later. As described in the single case report, we find thalamo‐frontal connectivity to be increased at the chronic, compared with the acute, time‐point. The increased connectivity was independent of whether patients had already recovered consciousness prior to the first assessment or whether they recovered consciousness in‐between the two. Conversely, we did find an association between restoration of thalamo‐frontal connectivity and the return of complex cognitive function. While we did replicate the findings of Laureys et al. ( ), our data suggests that the restoration of thalamo‐frontal connectivity is not as tightly linked to the reemergence of consciousness per se. However, the degree to which the return of connectivity is linked to the return of complex cognitive function, or to the evolution of other time‐dependent post‐injury mechanisms, remains to be understood.