The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson’s disease

Acknowledgements The authors thank Benjamin Rahm (University of Freiburg) and Michael Fox (Harvard Medical School) for valuable comments on a previous version of this manuscript. This work was supported by a grant of the BrainLinks-BrainTools Cluster of Excellence funded by the German Research Foundation (DFG, grant number EXC 1086) to C.P.K., F.A., T.P., B.O.S., C.W, and V.A.C.; A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381 – TRR 295) as well as Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND). Funding Open Access funding enabled and organized by Projekt DEAL.Peer reviewedPublisher PD

Functionally dissociating ventro-dorsal components within the rostro-caudal hierarchical organization of the human prefrontal cortex

This work was supported by a grant of the BrainLinks-BrainTools Cluster of Excellence funded by the German Research Foundation (DFG, grant number EXC 1086).Peer reviewedPostprin

The Organization of Corticostriatal Connectivity in the Human Brain

Neurological and psychiatric disorders reveal that the basal ganglia subserve diverse functional domains, including movement, reward, and cognitive disorders (e.g., Parkinson's disease, addiction, schizophrenia). Monkey anatomical studies show that the striatum, the input structure of the basal ganglia, receives projections from nearly the entire cerebral cortex with a broad topography of motor, limbic, and association zones. However, until recently, non-invasive methods have not been available to conduct the complete mapping of the cortex to the striatum in humans. The development of functional connectivity magnetic resonance imaging (fcMRI) now allows the identification of functional connections in humans. The present dissertation reports two studies that first create a complete map of corticostriatal connectivity and then more closely examine striatal connectivity with association networks underlying cognition

Executive control and decision-making in the prefrontal cortex

The prefrontal cortex (PFC) subserves decision-making and executive control. Here we review recent empirical and modeling works with a focus on neuroimaging studies, which start unifying these two conceptual approaches of PFC function. We propose that the PFC comprises two arbitration systems: (1) a peripheral system comprising premotor/caudal PFC regions and orbitofrontal regions involved in the selection of actions based on perceptual cues and reward values, respectively, and embedded in behavioral sets associated with external contingencies inferred as being stable; (2) a core system comprising ventromedial, dorsomedial, lateral and polar PFC regions involved in superordinate probabilistic reasoning for arbitrating online between exploiting/adjusting previously learned behavioral sets and exploring/creating new ones for efficient adaptive behavior in variable and open-ended environments

Development of abstract thinking during childhood and adolescence: the role of rostrolateral prefrontal cortex

Rostral prefrontal cortex (RPFC) has increased in size and changed in terms of its cellular organisation during primate evolution. In parallel emerged the ability to detach oneself from the immediate environment to process abstract thoughts and solve problems and to understand other individuals’ thoughts and intentions. Rostrolateral prefrontal cortex (RLPFC) is thought to play an important role in supporting the integration of abstract, often self-generated, thoughts. Thoughts can be temporally abstract and relate to long term goals, or past or future events, or relationally abstract and focus on the relationships between representations rather than simple stimulus features. Behavioural studies have provided evidence of a prolonged development of the cognitive functions associated with RLPFC, in particular logical and relational reasoning, but also episodic memory retrieval and prospective memory. Functional and structural neuroimaging studies provide further support for a prolonged development of RLPFC during adolescence, with some evidence of increased specialisation of RLPFC activation for relational integration and aspects of episodic memory retrieval. Topics for future research will be discussed, such as the role of medial RPFC in processing abstract thoughts in the social domain, the possibility of training abstract thinking in the domain of reasoning, and links to education

Measuring visual stimulation and attention signals in human superior colliculus using high-resolution fMRI

textThe superior colliculus (SC) is a laminated oculomotor structure in the midbrain. In non-human primates SC has long been known to contain a retinotopically-organized map of visual stimulation in its superficial layers, which is aligned to a map of saccadic eye movements in the deeper layers. Microstimulation and electrophysiology experiments have shown that SC also plays a key role in covert visuospatial attention and suggest that attentional modulation also occurs in a retinotopic manner. Retinotopic organization of the visual field can be non-invasively mapped in humans using functional MRI with a technique called phase-encoded retinotopy. In this technique, rotating wedges and expanding rings of visual stimuli are used to map the polar angle and eccentricity dimensions of a polar coordinates system, respectively. A similar technique can also be used to map spatial attention by keeping the visual stimulus constant and cueing subjects to attend to apertures of rotating wedges and expanding rings within the stimulus. A previous study using fMRI has shown the polar angle representation of visual stimulation in human SC but was unable to find a representation of eccentricity. This work uses high-resolution fMRI along with special surface analysis techniques developed in our lab to demonstrate maps of both polar angle and eccentricity for visual stimulation. Moreover, visual attention is also shown to be topographically organized within SC and in registration with visual stimulation. Finally, in human visual cortex, fMRI is known to show activity for sustained spatial attention even in the absence of a significant visual stimulus, an attentional "base response". In this work, SC is shown to exhibit a similar sustained attention base response using a threshold-contrast detection paradigm. This base response was compared with a response for attention with visual stimulation. The peak amplitude of the base response occurred more deeply within SC tissue than the peak for attention with stimulation. It is proposed that this reflects the specific attentional enhancement of the deeper visuomotor neurons, which are hypothesized to be a direct neuronal correlate of the oculomotor theory of attention.Psycholog

A Deficit in Parvalbumin-Expressing Interneurons in the Hippocampus Leads to Physiological and Behavioral Phenotypes Relevant to Schizophrenia in a Genetic Mouse Model

Hippocampal GABAergic interneuron deficits are implicated in the pathophysiology of schizophrenia. Postmortem histological analyses show alteration in number and/or function of parvalbumin-expressing (PV+) GABAergic interneurons in the cerebral cortex of these patients. A parallel line of research using functional imaging of cerebral blood flow or volume has shown that hyperactivity of the hippocampus may contribute to psychotic symptoms as well as cognitive deficits in schizophrenia. It is not known if changes in GABA transmission, particularly in the number and function of PV+ interneurons, are causally related to hippocampal hyperactivity and expression of behavioral and cognitive abnormalities in schizophrenia. To help answer this question, we used genetic mouse models with deficits in cortical GABAergic interneuron development to test the hypothesis that a selective deficit in PV+ interneurons in the hippocampus can lead to schizophrenia relevant phenotypes such as hippocampal hyperactivity, dysregulation of the mesolimbic dopamine system, enhanced psychomotor responsiveness to amphetamine, and disruption of hippocampal dependent cognition. Here I describe my studies primarily on a mouse model with a deletion of the cell-cycle gene cyclin D2 (cD2 null). This mutation disrupts interneuron development in the medial ganglionic eminence (MGE), leading to a partial and selective deficit in PV+ interneurons in the neocortex and the hippocampus. I show that the cD2 null mouse shows regionally heterogeneous, persistent structural and functional deficit in PV+ interneurons, with a relatively larger and more functional deficit in the hippocampus. The GABAergic deficit in the hippocampus is associated with signs of disinhibition, such as increased cerebral blood volume as found by functional magnetic resonance imaging (fMRI).Upon establishing the evidence for hippocampal disinhibition in the cyclin D2 null mouse, I examined the relationship between this disinhibition and two areas of neural function know to be altered in psychosis and schizophrenia: Mesostriatal DA system function and hippocampus-mediated cognition. I found that the cD2 null mice showed increased dopamine population activity in the ventral tegmental area and enhanced psychomotor response to amphetamine. The latter was eliminated by a partial lesion of the ventral hippocampus, indicating hippocampal disinhibition as the driver of DA neuron dysregulation. In addition, cD2 null mice showed deficits in cognitive functions that recruit and depend on the hippocampus, such as the contextual and cued fear conditioning. Lastly, to test for a causal relationship between the PV+ interneuron deficit in the hippocampus, and the abnormalities in hippocampal metabolism, imaging phenotype, the mesolimbic dopamine dysfunction and contextual learning and memory, I examined the effects of replacing GABAergic interneurons to the hippocampus. I used transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) into the adult hippocampus of cyclin D2 null mutants. MGE-derived progenitor cells developed into structurally and functionally mature PV+ and other GABAergic cells, and normalized hippocampal hypermetabolism. In addition, the MGE transplants normalized VTA dopamine cell activity, normalized amphetamine sensitivity and improved hippocampus-dependent learning and memory. Taken together, these studies establish the plausibility of a causal relationship between hippocampal PV+ interneuron pathology and psychosis-relevant pathophysiological and cognitive phenotypes. Moreover, they provide a rationale for limbic cortical GABAergic-interneuron-targeted treatment strategies in psychotic disorders