About Us

The papers listed here have appeared during the five decades from the 1970s to the 2010s. Some have become difficult to access in original form. The articles cover diverse areas of cognitive neurology and behavioral neuroanatomy. The purpose of this website is to classify them by topic area in downloadable form. The resolution of the files, especially of early publications related to neuroanatomy, leaves a lot to be desired. Those interested in the fine resolution of axons, neurons and immunohistochemical labeling will need to hunt for the originals in library stacks.

Large-scale Networks and Theory of Cortical Function

The term ‘large scale neurocognitive network’ was introduced in 1990. The approach was built upon Geschwind’s ‘Disconnection Syndromes’ and combined the disconnection concept with developments derived from axonal tracing experiments and single unit recordings in monkeys. The cerebral cortex was parcellated into primary, unimodal, heteromodal, paralimbic and limbic components. These 5 zones collectively supported a hierarchy of information processing from sensory inputs to unimodal percepts and transmodal concepts. The obligatory synaptic stages inserted between sensory and limbic areas offered the primate brain the capacity for delaying stimulus-bound instinctual responses and enabled the ‘intermediate processing’ that we identify as thought, foresight, etc. Networks were conceptualized as interconnected epicenters where each anatomical component played an essential role for some behavioral components of the relevant domain and ancillary roles for the others. 

Neuroanatomy

Novel methods were developed for mapping the connections of the monkey brain with axonally transported tracers in combination with the immunohistochemical characterization of neurons. The tracing of frontoparietal connections clarified the anatomical foundations of the spatial attention network. They also provided the first definitive demonstration of monosynaptic projections from the inferior parietal lobule to paralimbic cortex in the cingulate gyrus. Another group of investigations explored the cytoarchitecture and connectivity of paralimbic areas in the insula, orbitofrontal cortex and temporal pole. These paralimbic areas link high order association cortex to core limbic areas. Their functions are highly heterogeneous and encompass aspects of behavior where cognition is modulated by emotion and motivation.

Network for Spatial Attention

A network revolving around three interconnected epicenters (parietal, frontal, cingulate) was delineated based on the neurological syndrome of hemispatial neglect and experimental work on monkeys. The parietal component of this network provides a map of perceptual salience; the frontal component enables the exploration of this landscape through active search; and the cingulate component provides a map of motivational relevance. Damage to any of these three epicenters leads to contralesional neglect syndromes that display perceptual, exploratory and motivational devaluations of the contralesional hemispace.

Cholinergic Systems

In the past, the term ‘ascending reticular activating system’ (ARAS) designated a reticulo-thalamo-cortical axis that enhanced arousal. Novel methods demonstrated an extrathalamic component of ARAS that originated in the locus coeruleus (noradrenergic), brainstem raphe (serotonergic), and basal forebrain (cholinergic). The cholinergic component of this extrathalamic reticular activating system is by far the most prominent. Its origin in the basal forebrain was designated Ch4 (nucleus basalis) within a system that classified 8 cholinergic nuclei (Ch1-Ch8) according to projection targets. Immunohistochemical investigations in the human brain showed a dense web of cholinergic axons in all cortical areas but with a gradient of density that was highest within limbic areas. Limbic areas were also the only parts of cortex with prominent projections back to the nucleus basalis. The cholinergic innervation of the cerebral cortex is thus poised to modulate cortical responsivity (probably through a regulation of the signal to noise ratio) in ways that reflect the prevailing limbic state.

Primary Progressive Aphasia

A neurodegenerative syndrome of initially isolated and progressive language impairment was designated ‘primary progressive aphasia’ (PPA).  The identification of this syndrome enabled the differentiation of these patients from typical amnestic forms of dementia. Investigations of PPA led to new insights on the organization of the left hemisphere language network; revealed the probabilistic relationship between clinical syndromes and underlying neuropathology; and demonstrated the heterogeneity of Alzheimer’s disease (also see next section).

Brain Aging and Dementia

The discovery of autosomal dominant forms of Alzheimer’s disease generated the belief that the pathophysiology was uniform and that the prime mover was an amyloidopathy. This belief is no longer universal. Sporadic, late onset forms of Alzheimer’s disease continue to raise unanswered questions: what is the role of age, why is the entorhinal area so vulnerable, how is the amyloid related to the neurofibrillary tangle, why does the neurodegeneration seem to progress along axonal projection pathways? These questions were addressed from multiple vantage points encompassing primary progressive aphasia, exceptional cognitive aging and the timing of the cholinergic and noradrenergic lesions.  A curious finding that still awaits a coherent explanation (and that may elucidate why patients respond to cholinesterase inhibitors even when cholinergic fibers are destroyed) is the presence of cholinesterase activity in all lesions associated with Alzheimer’s disease, including plaques, tangles and amyloid angiopathy.