Michael Peer

Brain system for mental orientation in space, time, and person

Significance Processing of spatial, temporal, and social relations relies on mental cognitive maps, on which the behaving self is oriented relative to different places, events, and people. Using high-resolution functional MRI scanning in individual subjects, we show that mental orientation in space, time, and person produces a sequential posterior–anterior pattern of activity in each participant’s brain. These activations are adjacent and partially overlapping, highlighting the relation between mental orientation in these domains. Furthermore, the activity is highly overlapping with the brain’s default-mode network, a system involved in self-referential processing. These findings may shed new light on fundamental cognitive processing of space, time, and person and alter our understanding of disorientation phenomena in neuropsychiatric disorders such as Alzheimer’s disease. Orientation is a fundamental mental function that processes the relations between the behaving self to space (places), time (events), and person (people). Behavioral and neuroimaging studies have hinted at interrelations between processing of these three domains. To unravel the neurocognitive basis of orientation, we used high-resolution 7T functional MRI as 16 subjects compared their subjective distance to different places, events, or people. Analysis at the individual-subject level revealed cortical activation related to orientation in space, time, and person in a precisely localized set of structures in the precuneus, inferior parietal, and medial frontal cortex. Comparison of orientation domains revealed a consistent order of cortical activity inside the precuneus and inferior parietal lobes, with space orientation activating posterior regions, followed anteriorly by person and then time. Core regions at the precuneus and inferior parietal lobe were activated for multiple orientation domains, suggesting also common processing for orientation across domains. The medial prefrontal cortex showed a posterior activation for time and anterior for person. Finally, the default-mode network, identified in a separate resting-state scan, was active for all orientation domains and overlapped mostly with person-orientation regions. These findings suggest that mental orientation in space, time, and person is managed by a specific brain system with a highly ordered internal organization, closely related to the default-mode network.

Reversible functional connectivity disturbances during transient global amnesia.

Transient global amnesia (TGA), an abrupt occurrence of severe anterograde episodic amnesia accompanied by repetitive questioning, has been known for more than 50 years. Despite extensive research, there is no clear evidence for the underlying pathophysiological basis of TGA. Moreover, there is no neuroimaging method to evaluate TGA in real time.

Neonatal Gene Therapy of Glycogen Storage Disease Type Ia Using a Feline Immunodeficiency Virus-based Vector

Glycogen storage disease type Ia (GSD-Ia), also known as von Gierke disease, is caused by a deficiency of glucose-6-phosphatase-alpha (G6Pase), a key enzyme in glucose homeostasis. From birth, affected individuals cannot maintain normal blood glucose levels and suffer from a variety of metabolic disorders, leading to life-threatening complications. Gene therapy has been proposed as a possible option for treatment of this illness. Vectors have been constructed from feline immunodeficiency virus (FIV), a nonprimate lentivirus, because the wild-type virus does not cause disease in humans. Previously, we have shown that these vectors are capable of integrating stably into hepatocyte cell lines and adult murine livers and lead to long-term transgene expression. In the current work, we have assessed the ability to attenuate disease symptoms in a murine model of GSD-Ia. Single administration of FIV vectors containing the human G6Pase gene to G6Pase-alpha(-/-) mice did not change the biochemical and pathological phenotype. However, a double neonatal administration protocol led to normalized blood glucose levels, significantly extended survival, improved body weight, and decreased accumulation of liver glycogen associated with the disease. This approach shows a promising paradigm for treating GSD-Ia patients early in life thereby avoiding long-term consequences.Glycogen storage disease type Ia (GSD-Ia), also known as von Gierke disease, is caused by a deficiency of glucose-6-phosphatase-α (G6Pase), a key enzyme in glucose homeostasis. From birth, affected individuals cannot maintain normal blood glucose levels and suffer from a variety of metabolic disorders, leading to life-threatening complications. Gene therapy has been proposed as a possible option for treatment of this illness. Vectors have been constructed from feline immunodeficiency virus (FIV), a nonprimate lentivirus, because the wild-type virus does not cause disease in humans. Previously, we have shown that these vectors are capable of integrating stably into hepatocyte cell lines and adult murine livers and lead to long-term transgene expression. In the current work, we have assessed the ability to attenuate disease symptoms in a murine model of GSD-Ia. Single administration of FIV vectors containing the human G6Pase gene to G6Pase-α-/- mice did not change the biochemical and pathological phenotype. However, a double neonatal administration protocol led to normalized blood glucose levels, significantly extended survival, improved body weight, and decreased accumulation of liver glycogen associated with the disease. This approach shows a promising paradigm for treating GSD-Ia patients early in life thereby avoiding long-term consequences.

Evidence for functional networks within the human brain's white matter.

Investigation of the functional macro-scale organization of the human cortex is fundamental in modern neuroscience. Although numerous studies have identified networks of interacting functional modules in the gray-matter, limited research was directed to the functional organization of the white-matter. Recent studies have demonstrated that the white-matter exhibits blood oxygen level-dependent signal fluctuations similar to those of the gray-matter. Here we used these signal fluctuations to investigate whether the white-matter is organized as functional networks by applying a clustering analysis on resting-state functional MRI (RSfMRI) data from white-matter voxels, in 176 subjects (of both sexes). This analysis indicated the existence of 12 symmetrical white-matter functional networks, corresponding to combinations of white-matter tracts identified by diffusion tensor imaging. Six of the networks included interhemispheric commissural bridges traversing the corpus callosum. Signals in white-matter networks correlated with signals from functional gray-matter networks, providing missing knowledge on how these distributed networks communicate across large distances. These findings were replicated in an independent subject group and were corroborated by seed-based analysis in small groups and individual subjects. The identified white-matter functional atlases and analysis codes are available at http://mind.huji.ac.il/white-matter.aspx. Our results demonstrate that the white-matter manifests an intrinsic functional organization as interacting networks of functional modules, similarly to the gray-matter, which can be investigated using RSfMRI. The discovery of functional networks within the white-matter may open new avenues of research in cognitive neuroscience and clinical neuropsychiatry. SIGNIFICANCE STATEMENT In recent years, functional MRI (fMRI) has revolutionized all fields of neuroscience, enabling identifications of functional modules and networks in the human brain. However, most fMRI studies ignored a major part of the brain, the white-matter, discarding signals from it as arising from noise. Here we use resting-state fMRI data from 176 subjects to show that signals from the human white-matter contain meaningful information. We identify 12 functional networks composed of interacting long-distance white-matter tracts. Moreover, we show that these networks are highly correlated to resting-state gray-matter networks, highlighting their functional role. Our findings enable reinterpretation of many existing fMRI datasets, and suggest a new way to explore the white-matter role in cognition and its disturbances in neuropsychiatric disorders.

Orientation and disorientation: lessons from patients with epilepsy.

Orientation in time, space, and person is a fundamental cognitive faculty and the bedrock of neurological and psychiatric mental status examination. Nevertheless, research in orientation and disorientation is neglected in both cognitive science and neuropsychiatry. Specifically, it is still unclear whether disorientations in time, space, and person represent a failure of the same system or merely share a common nomenclature and whether these three domains of orientation depend on different psychological and neural systems. Here, we analyzed descriptions of patients with specific orientation failures associated with circumscribed cortical lesions, with a primary focus on epilepsy. The form of disorientation is analyzed according to its specific domain, the underlying neuropsychiatric disorder, and its anatomical correlate. Disorientations in the different domains are classified as self-referenced (incorrect self-localization) or nonself-referenced (incorrect localization or knowledge of other places, events, and people). Analysis of the cognitive and neural systems disturbed in these patients suggests that disorientation in one or several domains may be related to a failure in a specific brain mechanism localized mostly in the right hemisphere, partially overlapping with the default mode network (mostly the medial and lateral parietal, medial temporal, and lateral prefrontal cortices), which processes essential self-related cognitive faculties such as orientation.

Intensity‐based masking: A tool to improve functional connectivity results of resting‐state fMRI

Seed‐based functional connectivity (FC) of resting‐state functional MRI data is a widely used methodology, enabling the identification of functional brain networks in health and disease. Based on signal correlations across the brain, FC measures are highly sensitive to noise. A somewhat neglected source of noise is the fMRI signal attenuation found in cortical regions in close vicinity to sinuses and air cavities, mainly in the orbitofrontal, anterior frontal and inferior temporal cortices. BOLD signal recorded at these regions suffers from dropout due to susceptibility artifacts, resulting in an attenuated signal with reduced signal‐to‐noise ratio in as many as 10% of cortical voxels. Nevertheless, signal attenuation is largely overlooked during FC analysis. Here we first demonstrate that signal attenuation can significantly influence FC measures by introducing false functional correlations and diminishing existing correlations between brain regions. We then propose a method for the detection and removal of the attenuated signal (“intensity‐based masking”) by fitting a Gaussian‐based model to the signal intensity distribution and calculating an intensity threshold tailored per subject. Finally, we apply our method on real‐world data, showing that it diminishes false correlations caused by signal dropout, and significantly improves the ability to detect functional networks in single subjects. Furthermore, we show that our method increases inter‐subject similarity in FC, enabling reliable distinction of different functional networks. We propose to include the intensity‐based masking method as a common practice in the pre‐processing of seed‐based functional connectivity analysis, and provide software tools for the computation of intensity‐based masks on fMRI data. Hum Brain Mapp 37:2407–2418, 2016.

Mental-orientation: A new approach to assessing patients across the Alzheimer’s disease spectrum.

Objective: This study aims to assess the role of mental-orientation in the diagnosis of mild cognitive impairment and Alzheimer’s disease using a novel task. Method: A behavioral study (Experiment 1) compared the mental-orientation task to standard neuropsychological tests in patients across the Alzheimer’s disease spectrum. A functional MRI study (Experiment 2) in young adults compared activations evoked by the mental-orientation and standard-orientation tasks as well as their overlap with brain regions susceptible to Alzheimer’s disease pathology. Results: The mental-orientation task differentiated mild cognitively impaired and healthy controls at 95% accuracy, while the Addenbrooke’s Cognitive Examination, Mini-Mental State Examination and standard-orientation achieved 74%, 70% and 50% accuracy, respectively. Functional MRI revealed the mental-orientation task to preferentially recruit brain regions exhibiting early Alzheimer’s-related atrophy, unlike the standard-orientation test. Conclusions: Mental-orientation is suggested to play a key role in Alzheimer’s disease, and consequently in early detection and follow-up of patients along the Alzheimer’s disease spectrum.

Self-reference, emotion inhibition and somatosensory disturbance: preliminary investigation of network perturbations in conversion disorder

Conversion disorder (CD), or functional neurological disorder, is manifested as a neurological disturbance that is not macroscopically visible on clinical structural neuroimaging and is instead ascribed to underlying psychological stress. Known for many years in neuropsychiatry, a comprehensive explanation of the way in which psychological stress leads to a neurological deficit of a structural‐like origin is still lacking.