Ventral prefrontal cortex structure and function in behavioural change

There is a considerable interest in the neural correlates of cognitive flexibility, language, valuation, credit assignment and decision-making. The ventrolateral, orbital and medial prefrontal cortex together with their long-range connections with the rest of the brain are thought to be critically involved in these cognitive processes. My thesis explores human and monkey ventrolateral, orbital and medial prefrontal cortex and their potential role in flexible adaptation and choice. In the introductory chapter I review neuroeconomic and neuro-ecological views of decision making, as well as modular versus connectionist views of brain structure and function. In the second and third chapter I investigate the connectivity of ventrolateral, orbital and medial prefrontal cortex and compare their sub-regions between humans and monkeys. Overall I report a striking degree of similarity of connectivity profiles across species even though these regions are thought to support uniquely human cognitive abilities such as language, social cognition, prospective planning and strategic decision-making. This may be taken to suggest that higher order cognitive functions “re-use” a neural apparatus that is shared with macaque monkeys. In the fourth chapter I present a parcellation of the white matter into the major long-range association fibre systems based on their projection patterns to the cortical surface. These findings may have implications not only for the cross-species comparison of connectivity-profiles but also for understanding some psychiatric and neurological disorders as "disconnection syndromes". I conclude by evaluating whether a modular view of brain structure and function is consistent with a view that portraits the brain as changeable, highly adaptive and strongly interconnected.</p

Functional and anatomical networks of executive control

Actions are selected in the context of environmental demands and internal goals. Both change constantly and dynamically and several studies have addressed the issue of how information about these is represented, updated and integrated in the brain to form appropriate decisions and actions. The reprogramming of actions requires inhibition of movements or movement plans, resolution of response conflict and initiation of alternative actions. The right inferior frontal cortex (rIFC) and the presupplementary motor areas (pre-SMA) have been suggested to play a major role in response inhibition and action reprogramming. The degree to which inhibition of actions at a behavioural level can be related to physiological inhibition is unknown.Using single and paired-pulse transcranial magnetic stimulation (TMS), we investigated M1 excitability and M1 internal inhibitory mechanisms during action reprogramming (see Chapter 2.1.1). The temporal pattern of M1 excitability and M1 internal inhibitory mechanisms differed from those during normal action execution and could therefore play a causal role in action reprogramming. These findings are important as M1 is likely to be the site of convergence from different influences exerted by regions in the frontal lobes.In a second experiment we used paired-pulse TMS over rIFC and M1 to investigate functional rIFC-M1 interactions (see 2.1.2). We found that rIFC inhibited M1 excitability 175 ms after cue onset only in trials when actions needed to be reprogrammed and responses had to be inhibited, but not during normal action selection.In a third experiment we used a combined paired-pulse TMS – diffusion tensor imaging (DTI) approach to elucidate anatomical pathways of functional pre-SMA-M1 and rIFC-M1 connectivity (see 2.2). We found extended networks of executive control and action reprogramming. These results suggest that both, pre-SMA and rIFC influence motor output via premotor areas and fronto-basal ganglia loops. Different latency periods of rIFC-M1 and pre-SMA-M1 interactions were mediated by different white matter paths and networks.In a fourth experiment we tried to delineate the roles of rIFC and pre-SMA during action reprogramming using a combined paired-pulse TMS– repetitive TMS paradigm (see 2.3). The inhibitory influence exerted by rIFC over M1 during action reprogramming disappeared after mild and transient disruption of pre-SMA activity.Besides elucidating a network of brain areas associated with action reprogramming and movement inhibition these experiments have interesting methodological implications.</p

Functional and anatomical networks of executive control

Actions are selected in the context of environmental demands and internal goals. Both change constantly and dynamically and several studies have addressed the issue of how information about these is represented, updated and integrated in the brain to form appropriate decisions and actions. The reprogramming of actions requires inhibition of movements or movement plans, resolution of response conflict and initiation of alternative actions. The right inferior frontal cortex (rIFC) and the presupplementary motor areas (pre-SMA) have been suggested to play a major role in response inhibition and action reprogramming. The degree to which inhibition of actions at a behavioural level can be related to physiological inhibition is unknown.Using single and paired-pulse transcranial magnetic stimulation (TMS), we investigated M1 excitability and M1 internal inhibitory mechanisms during action reprogramming (see Chapter 2.1.1). The temporal pattern of M1 excitability and M1 internal inhibitory mechanisms differed from those during normal action execution and could therefore play a causal role in action reprogramming. These findings are important as M1 is likely to be the site of convergence from different influences exerted by regions in the frontal lobes.In a second experiment we used paired-pulse TMS over rIFC and M1 to investigate functional rIFC-M1 interactions (see 2.1.2). We found that rIFC inhibited M1 excitability 175 ms after cue onset only in trials when actions needed to be reprogrammed and responses had to be inhibited, but not during normal action selection.In a third experiment we used a combined paired-pulse TMS – diffusion tensor imaging (DTI) approach to elucidate anatomical pathways of functional pre-SMA-M1 and rIFC-M1 connectivity (see 2.2). We found extended networks of executive control and action reprogramming. These results suggest that both, pre-SMA and rIFC influence motor output via premotor areas and fronto-basal ganglia loops. Different latency periods of rIFC-M1 and pre-SMA-M1 interactions were mediated by different white matter paths and networks.In a fourth experiment we tried to delineate the roles of rIFC and pre-SMA during action reprogramming using a combined paired-pulse TMS– repetitive TMS paradigm (see 2.3). The inhibitory influence exerted by rIFC over M1 during action reprogramming disappeared after mild and transient disruption of pre-SMA activity.Besides elucidating a network of brain areas associated with action reprogramming and movement inhibition these experiments have interesting methodological implications.This thesis is not currently available via ORA

Comparing brains by matching connectivity profiles

The great promise of comparative neuroscience is to understand why brains differ by investigating the relations between variations in the organization of different brains, their evolutionary history, and their current ecological niche. For this approach to be successful, the organization of different brains needs to be quantifiable. Here, we present an approach to formally comparing the connectivity of different cortical areas across different brains. We exploit the fact that cortical regions can be characterized by the unique pattern of connectivity, the so-called connectivity fingerprint. By comparing connectivity fingerprints between cortical areas in the human and non-human primate brain we can identify between-species homologs, but also illustrate that is driving differences between species. We illustrate the approach by comparing the organization of the frontal cortex between humans and macaques, showing general similarities combined with some differences in the lateral frontal pole

Causal manipulation of functional connectivity in a specific neural pathway during behaviour and at rest

Correlations in brain activity between two areas (functional connectivity) have been shown to relate to their underlying structural connections. We examine the possibility that functional connectivity also reflects short-term changes in synaptic efficacy. We demonstrate that paired transcranial magnetic stimulation (TMS) near ventral premotor cortex (PMv) and primary motor cortex (M1) with a short 8-ms inter-pulse interval evoking synchronous pre- and post-synaptic activity and which strengthens interregional connectivity between the two areas in a pattern consistent with Hebbian plasticity, leads to increased functional connectivity between PMv and M1 as measured with functional magnetic resonance imaging (fMRI). Moreover, we show that strengthening connectivity between these nodes has effects on a wider network of areas, such as decreasing coupling in a parallel motor programming stream. A control experiment revealed that identical TMS pulses at identical frequencies caused no change in fMRI-measured functional connectivity when the inter-pulse-interval was too long for Hebbian-like plasticity

Short-latency influence of medial frontal cortex on primary motor cortex during action selection under conflict

Medial frontal cortex (MFC) is crucial when actions have to be inhibited, reprogrammed, or selected under conflict, but the precise mechanism by which it operates is unclear. Importantly, how and when the MFC influences the primary motor cortex (M1) during action selection is unknown. Using paired-pulse transcranial magnetic stimulation, we investigated functional connectivity between the presupplementary motor area (pre-SMA) part of MFC and M1. We found that functional connectivity increased in a manner dependent on cognitive context: pre-SMA facilitated the motor evoked-potential elicited by M1 stimulation only during action reprogramming, but not when otherwise identical actions were made in the absence of conflict. The effect was anatomically specific to pre-SMA; it was not seen when adjacent brain regions were stimulated. We discuss implications for the anatomical pathways mediating the observed effects

Cutaneous Na(+) storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense

Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection