Publications by authors named "Vassilis E Koliatsos"

57 Publications

Toward a global and reproducible science for brain imaging in neurotrauma: the ENIGMA adult moderate/severe traumatic brain injury working group.

Brain Imaging Behav 2021 Apr;15(2):526-554

Department of Brain Sciences, Imperial College London, London, UK.

The global burden of mortality and morbidity caused by traumatic brain injury (TBI) is significant, and the heterogeneity of TBI patients and the relatively small sample sizes of most current neuroimaging studies is a major challenge for scientific advances and clinical translation. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Adult moderate/severe TBI (AMS-TBI) working group aims to be a driving force for new discoveries in AMS-TBI by providing researchers world-wide with an effective framework and platform for large-scale cross-border collaboration and data sharing. Based on the principles of transparency, rigor, reproducibility and collaboration, we will facilitate the development and dissemination of multiscale and big data analysis pipelines for harmonized analyses in AMS-TBI using structural and functional neuroimaging in combination with non-imaging biomarkers, genetics, as well as clinical and behavioral measures. Ultimately, we will offer investigators an unprecedented opportunity to test important hypotheses about recovery and morbidity in AMS-TBI by taking advantage of our robust methods for large-scale neuroimaging data analysis. In this consensus statement we outline the working group's short-term, intermediate, and long-term goals.
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http://dx.doi.org/10.1007/s11682-020-00313-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032647PMC
April 2021

Neuropsychiatry Coming of Age.

Psychiatr Clin North Am 2020 06;43(2):xiii-xiv

Neuropsychiatry Program, Sheppard Pratt Health System Departments of Pathology (Neuropathology), Neurology and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences, University of Maryland School of Medicine. Electronic address:

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http://dx.doi.org/10.1016/j.psc.2020.03.001DOI Listing
June 2020

The Behavioral Neuroscience of Traumatic Brain Injury.

Psychiatr Clin North Am 2020 06;43(2):305-330

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Traumatic brain injury is a calamity of various causes, pathologies, and extremely varied and often complex clinical presentations. Because of its predilection for brain systems underlying cognitive and complex behavioral operations, it may cause chronic and severe psychiatric illness that requires expert management. This is more so for the modern epidemic of athletic and military brain injuries which are dominated by psychiatric symptoms. Past medical, including psychiatric, history, and comorbidities are important and relevant for formulation and management. Traumatic brain injury is a model for other neuropsychiatric disorders and may serve as an incubator of new ideas for neurodegenerative disease.
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http://dx.doi.org/10.1016/j.psc.2020.02.009DOI Listing
June 2020

Update on the Neuropsychiatry of Substance Use Disorders.

Psychiatr Clin North Am 2020 06;43(2):291-304

Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuropsychiatry Program, Sheppard Pratt Health System, The Sheppard and Enoch Pratt Hospital, 6501 North Charles Street, Baltimore, MD 21204, USA.

This article reviews some of the recent discoveries about how neurobiological processes contribute to the understanding and treatment of substance use disorders. Particular focus is given to cannabis, opioids, and designer drugs. Important areas addressed include triggers and cravings, the central roles of dopamine and stress, and the endocannabinoid system. Clinical relevance of these findings for withdrawal management and relapse prevention is discussed. Also highlighted are issues related to the opioid epidemic and consequences both of continuing federal prohibition of cannabis as well as its state-by-state relaxation.
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http://dx.doi.org/10.1016/j.psc.2020.02.011DOI Listing
June 2020

Neuropsychiatry: Definitions, Concepts, and Patient Types.

Psychiatr Clin North Am 2020 06;43(2):213-227

Neuropsychiatry Program, Sheppard Pratt Health System, The Sheppard and Enoch Pratt Hospital, 6501 North Charles Street, Baltimore, MD 21204, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Neuropsychiatry is an integrative discipline defined by its history, its preferred patients, and its theoretic framework. Dealing with human behavior needs to consider the brain, but such consideration should avoid oversimplification: neurologic understanding is not essential, necessary, or desirable in all conditions encountered in clinical psychiatry. Neuropsychiatric theory is founded on discoveries in the areas of synaptic plasticity and cortical/limbic anatomy (bottom-up), but also evolutionary biology and anthropology (top-down). Going forward, we need to synthesize vital information, distinguish the essential from the trivial or tenuous, and remain open to dialogue with allied disciplines, our patients, and our students.
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http://dx.doi.org/10.1016/j.psc.2020.02.007DOI Listing
June 2020

Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury.

Mol Neurodegener 2019 11 27;14(1):44. Epub 2019 Nov 27.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Background: Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic axonal injury (TAI), which often leads to axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total axonal transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown.

Methods: Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and axonal degeneration in response to TAI.

Results: Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival.

Conclusion: The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.
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http://dx.doi.org/10.1186/s13024-019-0345-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882250PMC
November 2019

Optogenetically transduced human ES cell-derived neural progenitors and their neuronal progenies: Phenotypic characterization and responses to optical stimulation.

PLoS One 2019 11;14(11):e0224846. Epub 2019 Nov 11.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Optogenetically engineered human neural progenitors (hNPs) are viewed as promising tools in regenerative neuroscience because they allow the testing of the ability of hNPs to integrate within nervous system of an appropriate host not only structurally, but also functionally based on the responses of their differentiated progenies to light. Here, we transduced H9 embryonic stem cell-derived hNPs with a lentivirus harboring human channelrhodopsin (hChR2) and differentiated them into a forebrain lineage. We extensively characterized the fate and optogenetic functionality of hChR2-hNPs in vitro with electrophysiology and immunocytochemistry. We also explored whether the in vivo phenotype of ChR2-hNPs conforms to in vitro observations by grafting them into the frontal neocortex of rodents and analyzing their survival and neuronal differentiation. Human ChR2-hNPs acquired neuronal phenotypes (TUJ1, MAP2, SMI-312, and synapsin 1 immunoreactivity) in vitro after an average of 70 days of coculturing with CD1 astrocytes and progressively displayed both inhibitory and excitatory neurotransmitter signatures by immunocytochemistry and whole-cell patch clamp recording. Three months after transplantation into motor cortex of naïve or injured mice, 60-70% of hChR2-hNPs at the transplantation site expressed TUJ1 and had neuronal cytologies, whereas 60% of cells also expressed ChR2. Transplant-derived neurons extended axons through major commissural and descending tracts and issued synaptophysin+ terminals in the claustrum, endopiriform area, and corresponding insular and piriform cortices. There was no apparent difference in engraftment, differentiation, or connectivity patterns between injured and sham subjects. Same trends were observed in a second rodent host, i.e. rat, where we employed longer survival times and found that the majority of grafted hChR2-hNPs differentiated into GABAergic neurons that established dense terminal fields and innervated mostly dendritic profiles in host cortical neurons. In physiological experiments, human ChR2+ neurons in culture generated spontaneous action potentials (APs) 100-170 days into differentiation and their firing activity was consistently driven by optical stimulation. Stimulation generated glutamatergic and GABAergic postsynaptic activity in neighboring ChR2- cells, evidence that hChR2-hNP-derived neurons had established functional synaptic connections with other neurons in culture. Light stimulation of hChR2-hNP transplants in vivo generated complicated results, in part because of the variable response of the transplants themselves. Our findings show that we can successfully derive hNPs with optogenetic properties that are fully transferrable to their differentiated neuronal progenies. We also show that these progenies have substantial neurotransmitter plasticity in vitro, whereas in vivo they mostly differentiate into inhibitory GABAergic neurons. Furthermore, neurons derived from hNPs have the capacity of establishing functional synapses with postsynaptic neurons in vitro, but this outcome is technically challenging to explore in vivo. We propose that optogenetically endowed hNPs hold great promise as tools to explore de novo circuit formation in the brain and, in the future, perhaps launch a new generation of neuromodulatory therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844486PMC
March 2020

Wallerian degeneration as a therapeutic target in traumatic brain injury.

Curr Opin Neurol 2019 12;32(6):786-795

Department of Pathology, Division of Neuropathology.

Purpose Of Review: Diffuse or traumatic axonal injury is one of the principal pathologies encountered in traumatic brain injury (TBI) and the resulting axonal loss, disconnection, and brain atrophy contribute significantly to clinical morbidity and disability. The seminal discovery of the slow Wallerian degeneration mice (Wld) in which transected axons do not degenerate but survive and function independently for weeks has transformed concepts on axonal biology and raised hopes that axonopathies may be amenable to specific therapeutic interventions. Here we review mechanisms of axonal degeneration and also describe how these mechanisms may inform biological therapies of traumatic axonopathy in the context of TBI.

Recent Findings: In the last decade, SARM1 [sterile a and Toll/interleukin-1 receptor (TIR) motif containing 1] and the DLK (dual leucine zipper bearing kinase) and LZK (leucine zipper kinase) MAPK (mitogen-activated protein kinases) cascade have been established as the key drivers of Wallerian degeneration, a complex program of axonal self-destruction which is activated by a wide range of injurious insults, including insults that may otherwise leave axons structurally robust and potentially salvageable. Detailed studies on animal models and postmortem human brains indicate that this type of partial disruption is the main initial pathology in traumatic axonopathy. At the same time, the molecular dissection of Wallerian degeneration has revealed that the decision that commits axons to degeneration is temporally separated from the time of injury, a window that allows potentially effective pharmacological interventions.

Summary: Molecular signals initiating and triggering Wallerian degeneration appear to be playing an important role in traumatic axonopathy and recent advances in understanding their nature and significance is opening up new therapeutic opportunities for TBI.
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http://dx.doi.org/10.1097/WCO.0000000000000763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147987PMC
December 2019

Primary Traumatic Axonopathy in Mice Subjected to Impact Acceleration: A Reappraisal of Pathology and Mechanisms with High-Resolution Anatomical Methods.

J Neurosci 2018 04 22;38(16):4031-4047. Epub 2018 Mar 22.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,

Traumatic axonal injury (TAI) is a common neuropathology in traumatic brain injury and is featured by primary injury to axons. Here, we generated TAI with impact acceleration of the head in male transgenic mice in which specific populations of neurons and their axons are labeled with yellow fluorescent protein. This model results in axonal lesions in multiple axonal tracts along with blood-brain barrier disruption and neuroinflammation. The corticospinal tract, a prototypical long tract, is severely affected and is the focus of this study. Using optimized CLARITY at single-axon resolution, we visualized the entire corticospinal tract volume from the pons to the cervical spinal cord in 3D and counted the total number of axonal lesions and their progression over time. Our results divulged the presence of progressive traumatic axonopathy that was maximal at the pyramidal decussation. The perikarya of injured corticospinal neurons atrophied, but there was no evidence of neuronal cell death. We also used CLARITY at single-axon resolution to explore the role of the NMNAT2-SARM1 axonal self-destruction pathway in traumatic axonopathy. When we interfered with this pathway by genetically ablating SARM1 or by pharmacological strategies designed to increase levels of Nicotinamide (Nam), a feedback inhibitor of SARM1, we found a significant reduction in the number of axonal lesions early after injury. Our findings show that high-resolution neuroanatomical strategies reveal important features of TAI with biological implications, especially the progressive axonopathic nature of TAI and the role of the NMNAT2-SARM1 pathway in the early stages of axonopathy. In the first systematic application of novel high-resolution neuroanatomical tools in neuropathology, we combined CLARITY with 2-photon microscopy, optimized for detection of single axonal lesions, to reconstruct the injured mouse brainstem in a model of traumatic axonal injury (TAI) that is a common pathology associated with traumatic brain injury. The 3D reconstruction of the corticospinal tract at single-axon resolution allowed for a more advanced level of qualitative and quantitative understanding of TAI. Using this model, we showed that TAI is an axonopathy with a prominent role of the NMNAT2-SARM1 molecular pathway, that is also implicated in peripheral neuropathy. Our results indicate that high-resolution anatomical models of TAI afford a level of detail and sensitivity that is ideal for testing novel molecular and biomechanical hypotheses.
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http://dx.doi.org/10.1523/JNEUROSCI.2343-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705930PMC
April 2018

Preclinical modelling of militarily relevant traumatic brain injuries: Challenges and recommendations for future directions.

Brain Inj 2017 ;31(9):1168-1176

s Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research ; Silver Spring , MD , USA.

As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.
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http://dx.doi.org/10.1080/02699052.2016.1274779DOI Listing
June 2018

Task-based statistical image reconstruction for high-quality cone-beam CT.

Phys Med Biol 2017 Nov 1;62(22):8693-8719. Epub 2017 Nov 1.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, United States of America.

Task-based analysis of medical imaging performance underlies many ongoing efforts in the development of new imaging systems. In statistical image reconstruction, regularization is often formulated in terms to encourage smoothness and/or sharpness (e.g. a linear, quadratic, or Huber penalty) but without explicit formulation of the task. We propose an alternative regularization approach in which a spatially varying penalty is determined that maximizes task-based imaging performance at every location in a 3D image. We apply the method to model-based image reconstruction (MBIR-viz., penalized weighted least-squares, PWLS) in cone-beam CT (CBCT) of the head, focusing on the task of detecting a small, low-contrast intracranial hemorrhage (ICH), and we test the performance of the algorithm in the context of a recently developed CBCT prototype for point-of-care imaging of brain injury. Theoretical predictions of local spatial resolution and noise are computed via an optimization by which regularization (specifically, the quadratic penalty strength) is allowed to vary throughout the image to maximize local task-based detectability index ([Formula: see text]). Simulation studies and test-bench experiments were performed using an anthropomorphic head phantom. Three PWLS implementations were tested: conventional (constant) penalty; a certainty-based penalty derived to enforce constant point-spread function, PSF; and the task-based penalty derived to maximize local detectability at each location. Conventional (constant) regularization exhibited a fairly strong degree of spatial variation in [Formula: see text], and the certainty-based method achieved uniform PSF, but each exhibited a reduction in detectability compared to the task-based method, which improved detectability up to ~15%. The improvement was strongest in areas of high attenuation (skull base), where the conventional and certainty-based methods tended to over-smooth the data. The task-driven reconstruction method presents a promising regularization method in MBIR by explicitly incorporating task-based imaging performance as the objective. The results demonstrate improved ICH conspicuity and support the development of high-quality CBCT systems.
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http://dx.doi.org/10.1088/1361-6560/aa90fdDOI Listing
November 2017

Enhancing oligodendrocyte differentiation by transient transcription activation via DNA nanoparticle-mediated transfection.

Acta Biomater 2017 05 23;54:249-258. Epub 2017 Mar 23.

Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Materials Science & Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address:

Current approaches to derive oligodendrocytes from human pluripotent stem cells (hPSCs) need extended exposure of hPSCs to growth factors and small molecules, which limits their clinical application because of the lengthy culture time required and low generation efficiency of myelinating oligodendrocytes. Compared to extrinsic growth factors and molecules, oligodendrocyte differentiation and maturation can be more effectively modulated by regulation of the cell transcription network. In the developing central nervous system (CNS), two basic helix-loop-helix transcription factors, Olig1 and Olig2, are decisive in oligodendrocyte differentiation and maturation. Olig2 plays a critical role in the specification of oligodendrocytes and Olig1 is crucial in promoting oligodendrocyte maturation. Recently viral vectors have been used to overexpress Olig2 and Olig1 in neural stem/progenitor cells (NSCs) to induce the maturation of oligodendrocytes and enhance the remyelination activity in vivo. Because of the safety issues with viral vectors, including the insertional mutagenesis and potential tumor formation, non-viral transfection methods are preferred for clinical translation. Here we report a poly(β-amino ester) (PBAE)-based nanoparticle transfection method to deliver Olig1 and Olig2 into human fetal tissue-derived NSCs and demonstrate efficient oligodendrocyte differentiation following transgene expression of Olig1 and Olig2. This approach is potentially translatable for engineering stem cells to treat injured or diseased CNS tissues.

Statement Of Significance: Current protocols to derive oligodendrocytes from human pluripotent stem cells (hPSCs) require lengthy culture time with low generation efficiencies of mature oligodendrocytes. We described a new approach to enhance oligodendrocyte differentiation through nanoparticle-mediated transcription modulation. We tested an effective transfection method using cell-compatible poly (β-amino ester) (PBAE)/DNA nanoparticles as gene carrier to deliver transcription factor Olig1 and Olig2 into human fetal tissue-derived neural stem/progenitor cells, and showed efficient oligodendrocyte differentiation following transgene expression of Olig1 and Olig2. We believe that this translatable approach can be applied to many other cell-based regenerative therapies as well.
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http://dx.doi.org/10.1016/j.actbio.2017.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485910PMC
May 2017

Multi-resolution statistical image reconstruction for mitigation of truncation effects: application to cone-beam CT of the head.

Phys Med Biol 2017 01 29;62(2):539-559. Epub 2016 Dec 29.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore MD 21205, USA.

A prototype cone-beam CT (CBCT) head scanner featuring model-based iterative reconstruction (MBIR) has been recently developed and demonstrated the potential for reliable detection of acute intracranial hemorrhage (ICH), which is vital to diagnosis of traumatic brain injury and hemorrhagic stroke. However, data truncation (e.g. due to the head holder) can result in artifacts that reduce image uniformity and challenge ICH detection. We propose a multi-resolution MBIR method with an extended reconstruction field of view (RFOV) to mitigate truncation effects in CBCT of the head. The image volume includes a fine voxel size in the (inner) nontruncated region and a coarse voxel size in the (outer) truncated region. This multi-resolution scheme allows extension of the RFOV to mitigate truncation effects while introducing minimal increase in computational complexity. The multi-resolution method was incorporated in a penalized weighted least-squares (PWLS) reconstruction framework previously developed for CBCT of the head. Experiments involving an anthropomorphic head phantom with truncation due to a carbon-fiber holder were shown to result in severe artifacts in conventional single-resolution PWLS, whereas extending the RFOV within the multi-resolution framework strongly reduced truncation artifacts. For the same extended RFOV, the multi-resolution approach reduced computation time compared to the single-resolution approach (viz. time reduced by 40.7%, 83.0%, and over 95% for an image volume of 600, 800, 1000 voxels). Algorithm parameters (e.g. regularization strength, the ratio of the fine and coarse voxel size, and RFOV size) were investigated to guide reliable parameter selection. The findings provide a promising method for truncation artifact reduction in CBCT and may be useful for other MBIR methods and applications for which truncation is a challenge.
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http://dx.doi.org/10.1088/1361-6560/aa52b8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234681PMC
January 2017

Patient Profiles of Criminal Behavior in the Context of Traumatic Brain Injury.

J Forensic Sci 2017 Mar 16;62(2):545-548. Epub 2016 Nov 16.

The Neuropsychiatry Program at Sheppard Pratt, Sheppard Pratt Health System, 6501 North Charles Street, PO Box 6815, Baltimore, MD, 21285-6815.

Traumatic brain injury (TBI) can lead to significant post-traumatic disturbances in mood and behavior, with the frontal lobes playing a key role in emotional and behavioral regulation. Injury to the frontal lobe can result in disinhibition and aggression which can result in police intervention and/or incarceration. We highlight four adult cases with a history of severe TBI with frontal lobe injuries and the presence of post-TBI criminal behaviors. There is evidence to support an anatomical basis for aggressive behaviors, yet there are other risk factors to be considered. Behaviors must be investigated thoroughly by obtaining adequate pre- and post-TBI psychiatric and psychosocial histories. By having a comprehensive understanding of aggression while appreciating the complex relationship between TBI, aggression, and premorbid risk factors, clinicians can more adequately treat patients with TBI, with the aim of potentially preventing criminal behaviors and recidivism.
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http://dx.doi.org/10.1111/1556-4029.13289DOI Listing
March 2017

Clinicopathological correlates of depression in early Alzheimer's disease in the NACC.

Int J Geriatr Psychiatry 2016 12 14;31(12):1301-1311. Epub 2016 Feb 14.

Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: Depression may be a prodrome to Alzheimer's disease (AD). We assessed whether AD neuropathology is associated with depression in mild cognitive impairment (MCI) and mild dementia (dAD).

Methods: All clinical and neuropathological data for this study came from the National Alzheimer's Coordinating Center (NACC). Healthy control (HC, n = 120), MCI (n = 77), and mild dAD (n = 93) patients who underwent brain autopsy were included. In regression models with Geriatric Depression Scale (GDS) as the outcome, neuritic plaque (NP) score or Braak Stages of neurofibrillary (NF) pathology were covariates.

Results: GDS was not associated with cognitive status, NP score, Braak Stages, or their interaction. In both models, a history of TIAs, depression within the last 2 years, current benzodiazepine use, and greater severity of neuropsychiatric symptoms were associated with greater depression. In the Braak Stages model, less education was another significant predictor.

Conclusions: Depression in early AD appears to be independent of NP and NF pathology. Studies are needed to investigate other mechanisms that may be responsible for depression in MCI and dAD.
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http://dx.doi.org/10.1002/gps.4435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983531PMC
December 2016

A Clinical Approach to Cognitive Impairment.

Focus (Am Psychiatr Publ) 2016 Oct 7;14(4):437-447. Epub 2016 Oct 7.

Dr. Koliatsos is the Stulman Scholar in Clinical Neuropsychiatry and Director, Neuropsychiatry Program, Sheppard and Enoch Pratt Hospital, Towson, Maryland; professor of Pathology and Neurology and associate professor of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore; and clinical professor of Psychiatry, University of Maryland School of Medicine, Baltimore (e-mail:

Cognitive impairment is ubiquitous in medicine and a common experience in everyday life. When severe, persistent, or progressive, it becomes a matter of clinical concern. Top causes of clinically significant cognitive impairment are neurodegenerative disease, stroke or atherosclerotic vascular disease of the brain, medication toxicity, and alcoholism. Several of these conditions are associated with aging of the population in industrialized nations, and they are comorbid with multiple other illnesses and polypharmacy. In evaluating such problems, history is paramount, including a detailed time course of symptoms and input from caregivers. Examination should include neurologic and mental status components and should be as thorough as possible. Ancillary testing should be strategic and address specific problems in the differential diagnosis. Appropriate referrals to other medical disciplines should be promptly arranged, with engagement of the primary care provider. The caregiver is often a hidden patient. The psychiatrist who works with cognitively impaired patients should stay abreast of developments in a rapidly evolving field and adopt a team approach to care with other clinical specialties and caregivers.
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http://dx.doi.org/10.1176/appi.focus.20160026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519596PMC
October 2016

LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1 -mediated signalling pathways.

Hum Mol Genet 2016 08 4;25(16):3515-3523. Epub 2016 Jul 4.

Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to Parkinson's disease (PD), the most common degenerative movement disorder. LRRK2 is expressed by both neurons and microglia, the residential immune cells in the brain. Increasing evidence supports a role of LRRK2 in modulating microglial activity, of which Lrrk2-null rodent microglia display less inflammatory response to endotoxin lipopolysaccharide (LPS). The underlying molecular mechanism, however, remains elusive. Chemokine (C-X3-C) receptor 1 (CX3CR1), predominantly expressed by microglia, suppresses microglial inflammation while promotes migration. Using whole-genome microarray screening, we found that Cx3cr1 mRNA levels were substantially higher in microglia derived from Lrrk2 knockout (Lrrk2) mice. The total and cell surface levels of CX3CR1 proteins were also remarkably increased. In correlation with the enhanced CX3CR1 expression, Lrrk2-null microglia migrated faster and travelled longer distance toward the source of fractalkine (CX3CL1), an endogenous ligand of CX3CR1. To investigate the impact of CX3CR1 elevation in vivo, we compared LPS-induced inflammation in the striatum of Lrrk2 knockout mice with Cx3cr1 heterozygous and homozygous knockout background. We found that a complete loss of Cx3cr1 restored the responsiveness of Lrrk2 microglia to LPS stimulation. In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia.
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http://dx.doi.org/10.1093/hmg/ddw194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179946PMC
August 2016

Neuroinflammation in primary blast neurotrauma: Time course and prevention by torso shielding.

Exp Neurol 2016 Mar 16;277:268-274. Epub 2016 Jan 16.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; National Security Technology, Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Mechanisms of primary blast injury caused by overpressure are not fully understood. In particular, the presence and time course of neuroinflammation are unknown and so are the signatures of reactive inflammatory cells, especially the neuroprotective versus injurious roles of microglia. In general, chronic microglial activation in the injured brain suggests a pro-degenerative role for these reactive cells. In this study, we investigated the temporal dynamics of microglial activation in the brain of mice exposed to mild-moderate blast in a shock tube. Because, in our previous work, we had found that torso shielding with rigid Plexiglas attenuates traumatic axonal injury in the brain, we also evaluated neuroinflammatory microglial responses in animals with torso protection at 7 days post blast injury. Because of the prominent involvement of the visual system in blast TBI in rodents, activated microglial cells were counted in the optic tract at various time points post-injury with stereological methods. Cell counts (activated microglial cell densities) from subjects exposed to blast TBI were compared with counts from corresponding sham animals. We found that mild-moderate blast injury causes focal activation of microglia in certain white matter tracts, including the visual pathway. In the optic tract, the density of activated microglial profiles gradually intensified from 3 to 15 days post-injury and then became attenuated at 30 days. Torso protection significantly reduced microglial activation at 7 days. These findings shed light into mechanisms of primary blast neurotrauma and may suggest novel diagnostic and monitoring methods for patients. They leave open the question of whether microglial activation post blast is protective or detrimental, although response is time limited. Finally, our findings confirm the protective role of torso shielding and stress the importance of improved or optimized body gear for warfighters or other individuals at risk for blast exposure.
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http://dx.doi.org/10.1016/j.expneurol.2016.01.010DOI Listing
March 2016

Stem cell therapies for traumatic brain injury.

Regen Med 2015 Nov 6;10(8):917-20. Epub 2015 Nov 6.

Departments of Physical & Medical Rehabilitation, Neurological Surgery, & Anatomy & Neurobiology, Sue & Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, CA 92697, USA.

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http://dx.doi.org/10.2217/rme.15.62DOI Listing
November 2015

Manganese-Enhanced Magnetic Resonance Imaging as a Diagnostic and Dispositional Tool after Mild-Moderate Blast Traumatic Brain Injury.

J Neurotrauma 2016 Apr 14;33(7):662-71. Epub 2015 Dec 14.

7 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Traumatic brain injury (TBI) caused by explosive munitions, known as blast TBI, is the signature injury in recent military conflicts in Iraq and Afghanistan. Diagnostic evaluation of TBI, including blast TBI, is based on clinical history, symptoms, and neuropsychological testing, all of which can result in misdiagnosis or underdiagnosis of this condition, particularly in the case of TBI of mild-to-moderate severity. Prognosis is currently determined by TBI severity, recurrence, and type of pathology, and also may be influenced by promptness of clinical intervention when more effective treatments become available. An important task is prevention of repetitive TBI, particularly when the patient is still symptomatic. For these reasons, the establishment of quantitative biological markers can serve to improve diagnosis and preventative or therapeutic management. In this study, we used a shock-tube model of blast TBI to determine whether manganese-enhanced magnetic resonance imaging (MEMRI) can serve as a tool to accurately and quantitatively diagnose mild-to-moderate blast TBI. Mice were subjected to a 30 psig blast and administered a single dose of MnCl2 intraperitoneally. Longitudinal T1-magnetic resonance imaging (MRI) performed at 6, 24, 48, and 72 h and at 14 and 28 days revealed a marked signal enhancement in the brain of mice exposed to blast, compared with sham controls, at nearly all time-points. Interestingly, when mice were protected with a polycarbonate body shield during blast exposure, the marked increase in contrast was prevented. We conclude that manganese uptake can serve as a quantitative biomarker for TBI and that MEMRI is a minimally-invasive quantitative approach that can aid in the accurate diagnosis and management of blast TBI. In addition, the prevention of the increased uptake of manganese by body protection strongly suggests that the exposure of an individual to blast risk could benefit from the design of improved body armor.
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http://dx.doi.org/10.1089/neu.2015.4002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827293PMC
April 2016

Evidence for accelerated tauopathy in the retina of transgenic P301S tau mice exposed to repetitive mild traumatic brain injury.

Exp Neurol 2015 Nov 24;273:168-76. Epub 2015 Aug 24.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI.
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http://dx.doi.org/10.1016/j.expneurol.2015.08.014DOI Listing
November 2015

Diagnostic and treatment challenges in traumatic brain injury patients with severe neuropsychiatric symptoms: insights into psychiatric practice.

Neuropsychiatr Dis Treat 2015 1;11:1601-7. Epub 2015 Jul 1.

The Neuropsychiatry Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD, USA.

Traumatic brain injury (TBI) causes a variety of neuropsychiatric problems that pose diagnostic and treatment challenges for providers. In this report, we share our experience as a referral neuropsychiatry program to assist the general psychiatrist when adult TBI patients with psychiatric symptoms present for evaluation and treatment. We completed a retrospective study of patients with moderate-to-severe TBI and severe neuropsychiatric impairments. We collected information on demographics, nature of injury, symptomatology, diagnoses, and treatments. Data analysis indicates that mood stabilization was a key concern, often requiring aggressive pharmacological management. Cognitive dysfunction was a problem for the majority of patients, but was only medicated in a third, due to poor efficacy or behavioral side effects. The co-occurrence of multiple TBI-related symptoms and diagnoses in this patient cohort emphasizes the need for individualized psychopharmacological approaches and interventions.
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http://dx.doi.org/10.2147/NDT.S80457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494623PMC
July 2015

Transplantation of human oligodendrocyte progenitor cells in an animal model of diffuse traumatic axonal injury: survival and differentiation.

Stem Cell Res Ther 2015 May 14;6:93. Epub 2015 May 14.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Introduction: Diffuse axonal injury is an extremely common type of traumatic brain injury encountered in motor vehicle crashes, sports injuries, and in combat. Although many cases of diffuse axonal injury result in chronic disability, there are no current treatments for this condition. Its basic lesion, traumatic axonal injury, has been aggressively modeled in primate and rodent animal models. The inexorable axonal and perikaryal degeneration and dysmyelination often encountered in traumatic axonal injury calls for regenerative therapies, including therapies based on stem cells and precursors. Here we explore the proof of concept that treatments based on transplants of human oligodendrocyte progenitor cells can replace or remodel myelin and, eventually, contribute to axonal regeneration in traumatic axonal injury.

Methods: We derived human oligodendrocyte progenitor cells from the human embryonic stem cell line H9, purified and characterized them. We then transplanted these human oligodendrocyte progenitor cells into the deep sensorimotor cortex next to the corpus callosum of nude rats subjected to traumatic axonal injury based on the impact acceleration model of Marmarou. We explored the time course and spatial distribution of differentiation and structural integration of these cells in rat forebrain.

Results: At the time of transplantation, over 90 % of human oligodendrocyte progenitor cells expressed A2B5, PDGFR, NG2, O4, Olig2 and Sox10, a profile consistent with their progenitor or early oligodendrocyte status. After transplantation, these cells survived well and migrated massively via the corpus callosum in both injured and uninjured brains. Human oligodendrocyte progenitor cells displayed a striking preference for white matter tracts and were contained almost exclusively in the corpus callosum and external capsule, the striatopallidal striae, and cortical layer 6. Over 3 months, human oligodendrocyte progenitor cells progressively matured into myelin basic protein(+) and adenomatous polyposis coli protein(+) oligodendrocytes. The injured environment in the corpus callosum of impact acceleration subjects tended to favor maturation of human oligodendrocyte progenitor cells. Electron microscopy revealed that mature transplant-derived oligodendrocytes ensheathed host axons with spiral wraps intimately associated with myelin sheaths.

Conclusions: Our findings suggest that, instead of differentiating locally, human oligodendrocyte progenitor cells migrate massively along white matter tracts and differentiate extensively into ensheathing oligodendrocytes. These features make them appealing candidates for cellular therapies of diffuse axonal injury aiming at myelin remodeling and axonal protection or regeneration.
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http://dx.doi.org/10.1186/s13287-015-0087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453242PMC
May 2015

Treatment of Traumatic Brain Injury-Induced Dyskinesia With Tetrabenazine: A Case Report.

Psychosomatics 2015 Sep-Oct;56(5):567-71. Epub 2014 Nov 6.

The Neuropsychiatry Program at Sheppard Pratt, Sheppard Pratt Health System, Baltimore, MD.

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http://dx.doi.org/10.1016/j.psym.2014.11.001DOI Listing
March 2016

Repetitive mild traumatic brain injury with impact acceleration in the mouse: Multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system.

Exp Neurol 2016 Jan 20;275 Pt 3:436-449. Epub 2014 Nov 20.

Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Repetitive mild traumatic brain injury (mTBI) is implicated in chronic neurological illness. The development of animal models of repetitive mTBI in mice is essential for exploring mechanisms of these chronic diseases, including genetic vulnerability by using transgenic backgrounds. In this study, the rat model of impact acceleration (IA) was redesigned for the mouse cranium and used in two clinically relevant repetitive mTBI paradigms. We first determined, by using increments of weight dropped from 1m that the 40g weight was most representative of mTBI and was not associated with fractures, brain contusions, anoxic-ischemic injury, mortality, or significant neurological impairments. Quantitative evaluation of traumatic axonal injury (TAI) in the optic nerve/tract, cerebellum and corpus callosum confirmed that weight increase produced a graded injury. We next evaluated two novel repetitive mTBI paradigms (1 time per day or 3 times per day at days 0, 1, 3, and 7) and compared the resulting TAI, neuronal cell death, and neuroinflammation to single hit mTBI at sub-acute (7days) and chronic time points (10weeks) post-injury. Both single and repetitive mTBI caused TAI in the optic nerve/tract, cerebellum, corticospinal tract, lateral lemniscus and corpus callosum. Reactive microglia with phagocytic phenotypes were present at injury sites. Severity of axonal injury corresponded to impact load and frequency in the optic nerve/tract and cerebellum. Both single and repeat injury protocols were associated with retinal ganglion cell loss and optic nerve degeneration; these outcomes correlated with impact load and number/frequency. No phosphorylated tau immunoreactivity was detected in the brains of animals subjected to repetitive mTBI. Our findings establish a new model of repetitive mTBI model featured by TAI in discrete CNS tracts, especially the visual system and cerebellum. Injury in retina and optic nerve provides a sensitive measure of severity of mTBI, thus enabling further studies on mechanisms and experimental therapeutics. Our model can also be useful in exploring mechanisms of chronic neurological disease caused by repetitive mTBI in wild-type and transgenic mice.
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http://dx.doi.org/10.1016/j.expneurol.2014.11.004DOI Listing
January 2016

The problem of axonal injury in the brains of veterans with histories of blast exposure.

Acta Neuropathol Commun 2014 Nov 25;2:153. Epub 2014 Nov 25.

Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Introduction: Blast injury to brain, a hundred-year old problem with poorly characterized neuropathology, has resurfaced as health concern in recent deployments in Iraq and Afghanistan. To characterize the neuropathology of blast injury, we examined the brains of veterans for the presence of amyloid precursor protein (APP)-positive axonal swellings typical of diffuse axonal injury (DAI) and compared them to healthy controls as well as controls with opiate overdose, anoxic-ischemic encephalopathy, and non-blast TBI (falls and motor vehicle crashes).

Results: In cases with blast history, we found APP (+) axonal abnormalities in several brain sites, especially the medial dorsal frontal white matter. In white matter, these abnormalities were featured primarily by clusters of axonal spheroids or varicosities in a honeycomb pattern with perivascular distribution. Axonal abnormalities colocalized with IBA1 (+) reactive microglia and had an appearance that was distinct from classical DAI encountered in TBI due to motor vehicle crashes. Opiate overdose cases also showed APP (+) axonal abnormalities, but the intensity of these lesions was lower compared to cases with blast histories and there was no clear association of such lesions with microglial activation.

Conclusions: Our findings demonstrate that many cases with history of blast exposure are featured by APP (+) axonopathy that may be related to blast exposure, but an important role for opiate overdose, antemortem anoxia, and concurrent blunt TBI events in war theater or elsewhere cannot be discounted.
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http://dx.doi.org/10.1186/s40478-014-0153-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260204PMC
November 2014

Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties.

Stem Cells Dev 2014 Dec;23(24):2996-3010

1 Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.

Although the majority of Alzheimer's disease (AD) cases are sporadic, about 5% of cases are inherited in an autosomal dominant pattern as familial AD (FAD) and manifest at an early age. Mutations in the presenilin 1 (PSEN1) gene account for the majority of early-onset FAD. Here, we describe the generation of virus-free human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of patients harboring the FAD PSEN1 mutation A246E and fibroblasts from healthy age-matched controls using nonintegrating episomal vectors. We have differentiated these hiPSC lines to the neuronal lineage and demonstrated that hiPSC-derived neurons have mature phenotypic and physiological properties. Neurons from mutant hiPSC lines express PSEN1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of amyloid precursor protein (APP) indicated by an increase in β-amyloid (Aβ)42/Aβ40 ratio. FAD hiPSCs harboring disease properties can be used as humanized models to test novel diagnostic methods and therapies and explore novel hypotheses for AD pathogenesis.
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http://dx.doi.org/10.1089/scd.2013.0511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267410PMC
December 2014

Remodeling of the piriform cortex after lesion in adult rodents.

Neuroreport 2014 Sep;25(13):1006-12

aDepartment of Pathology, Division of Neuropathology Departments of bNeurology cPsychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Denervation of the piriform cortex by bulbotomy causes a series of important cellular changes in the inhibitory interneurons of layer I and transsynaptic apoptosis of a large number of pyramidal neurons in outer layer II within 24 h. In this study, we report that following the marked loss of neurons in outer layer II, the piriform cortex is reconstituted by the addition of newly formed neurons that restore the number to a preinjury level within 30 days. We provide evidence that the number of newly divided neuronal progenitors increases after injury and further show that a population of doublecortin-positive cells that resides in the piriform cortex decreases after injury. Taken together, these findings suggest that the piriform cortex has significant neurogenic potential that is activated following sensory denervation and may contribute toward the replacement of neurons in outer layer II.
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http://dx.doi.org/10.1097/WNR.0000000000000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126869PMC
September 2014
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