Selected Works of Marsel Mesulam

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.

1. Mesulam M-M. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann Neurol 1990; 28(5): 597-613.
2. Mesulam M-M. Neurocognitive networks and selectively distributed processing. Rev Neurol (Paris) 1994; 150: 564-9.
3. Seeck M, Schomer D, Mainwaring N, Ives J, Dubuisson D, Blume H, Cosgrove R, Ransil BJ, Mesulam M-M. Selectively distributed processing of visual object recognition in the temporal and frontal lobes of the human brain. Ann Neurol 1995;37:538-545.
4. Mesulam M-M. From sensation to cognition. Brain 1998; 121: 1013-52.
5. Mesulam MM. Representation, inference and transcendent encoding in neurocognitive networks of the human brain. Ann Neurol 2008; 64: 367-78.
6. Mesulam M-M. Fifty years of disconnexion syndromes and the Geschwind legacy. Brain 2015; 138: 2791-9.
7. Mesulam M. Defining neurocognitive networks in the BOLD new world of computed connectivity. Neuron 2009;62:1-3.
8. Mesulam M-M. Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system and hemispheric specialization. In: Mesulam M-M, ed. Principles of Behavioral and Cognitive Neurology. New York: Oxford University Press, 2000: 1-120.

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.

1. Mesulam MM, Van Hoesen GW, Pandya DN, Geschwind N. Limbic and sensory connections of the inferior parietal lobule (area PG) in the rhesus monkey: a study with a new method for horseradish peroxidase histochemistry. Brain Res 1977; 136(3): 393-414.
2. Barbas H, Mesulam MM. Organization of afferent input to subdivisions of area 8 in the rhesus monkey. J Comp Neurol 1981;200:407-431.
3. Barbas H, Mesulam MM. Cortical afferent input to the principalis region of the rhesus monkey. Neuroscience 1985;15:619-637.
4. Mesulam M-M, Mufson EJ. Insula of the old world monkey. I. Architectonics in the insulo- orbito-temporal component of the paralimbic brain. J Comp Neurol 1982a; 212(1): 1-22.
5. Mufson EJ, Mesulam MM. Insula of the old world monkey. II: Afferent cortical input and comments on the claustrum. J Comp Neurol 1982;212:23-37.
6. Mesulam M-M, Mufson EJ. Insula of the old world monkey. III: Efferent cortical output and comments on function. J Comp Neurol 1982b; 212(1): 38-52.
7. Morecraft RJ, Geula C, Mesulam MM. Cytoarchitecture and neural afferents of orbitofrontal cortex in the brain of the monkey. J Comp Neurol 1992;323:341-358.
8. Morán MA, Mufson EJ, Mesulam MM. Neural inputs into the temporopolar cortex of the rhesus monkey. J Comp Neurol 1987;256:88-103.
9. Mesulam M. The evolving landscape of human cortical connectivity: Facts and inferences. NeuroImage 2012;62:2182-2189.
10. Price BH, Mesulam MM. Behavioral manifestations of central pontine myelinolysis. Arch Neurol 1987;44:671-673.

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.

1. Mesulam M-M. A cortical network for directed attention and unilateral neglect. Ann Neurol 1981;10:309-325.
2. Morecraft RJ, Geula C, Mesulam M-M. Architecture of connectivity within a cingulo-fronto-parietal neurocognitive network for directed attention. Arch Neurol 1993;50:279-284.
3. Gitelman DR, Nobre AC, Parrish TB, laBar KS, Kim Y-H, Meyer JR, Mesulam M-M. A large-scale distributed network for spatial attention: further anatomical delineation based on stringent behavioural and cognitive controls. Brain 1999;122:1093-1106.
4. Nobre AC, Coull JT, Maquet P, Frith CD, Vandenberghe R, Mesulam M-M. Orienting attention to locations in perceptual versus mental representations. J Cog Neurosci 2004;16:363-373.
5. Mesulam M-M. Spatial attention and neglect: parietal, frontal, and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events. Phil Trans Roy Soc B 1999;354:1325-1346.

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.

1. Mesulam MM, Van Hoesen GW. Acetylcholinesterase-rich projections from the basal forebrain of the rhesus monkey to neocortex. Brain Res 1976;109:152-157.
2. Mesulam M-M, Mufson EJ, Levey AI, Wainer BH. Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 1983;214:170-197.
3. Mesulam MM, Mufson EJ, Wainer BH, Levey AI. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 1983;10:1185-1201.
4. Mesulam M-M, Mufson EJ. Neural inputs into the nucleus basalis of the substantia innominata (Ch4) in the rhesus monkey. Brain 1984;107:253-274.
5. Mesulam M-M. Asymmetry of neural feedback in the organization of behavioral states. Science 1987;237:537-538.
6. Mesulam M-M, Geula C. Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 1988;275:216-240.
7. Smiley JF, Mesulam M-M. Cholinergic neurons of the nucleus basalis of Meynert (Ch4) receive cholinergic, catecholaminergic, and GABAergic synapses: an electron microscopic investigation in the monkey. Neuroscience 1999;88:241-255.
8. Smiley JF, Morrell F, Mesulam M-M. Cholinergic synapses in human cerebral cortex: an ultrastructural study in serial sections. Exper Neurol 1997;144:361-368.
9. Mesulam M-M, Hersh LB, Mash DC, Geula C. Differential cholinergic innervation within functional subdivisions of the human cerebral cortex: a choline acetyltransferase study. J Comp Neurol 1992;318:316-328.
10. Mesulam M-M, Geula C, Bothwell MA, Hersh LB. Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons. J Comp Neurol 1989;283:611-633.
11. Mesulam M-M, Mash D, Hersh L, Bothwell M, Geula C. Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus.  J Comp Neurol 1992;323:252-268.
12. Heckers S, Geula C, Mesulam MM. Cholinergic innervation of the human thalamus: dual origin and differential nuclear distribution. J Comp Neurol 1992;325:68-82.
13. Mesulam M-M. Cholinergic Circuitry of the human nucleus basalis and is fate in Alzheimer’s disease. J Comp Neurol 2013;521:4124-4144.

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).

1. Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann Neurol 1982;11:592-598.
2. Mesulam MM. Primary progressive aphasia–differentiation from Alzheimer’s disease [editorial]. Ann Neurol 1987;22:533-534.
3. Weintraub S, Rubin NP, Mesulam M-M. Primary progressive aphasia. Longitudinal course, neuropsychological profile, and language features. Arch Neurol 1990;47:1329-1335.
4. Rogalski E, Johnson N, Weintraub S, Mesulam M-M. Increased frequency of learning disability in patients with primary progressive aphasia and their first degree relatives. Arch Neurol 2008;65:244-248.
5. Mesulam M-M, Weintraub S, Rogalski EJ, Wieneke C, Geula C, Bigio EH. Asymmetry and heterogeneity of Alzheimer and frontotemporal pathology in primary progressive aphasia. Brain 2014.
6. Gefen T, Gasho K, Rademaker A, Lalehzari M, Weintraub S, Rogalski E, Wieneke C, Bigio E, Geula G, Mesulam M-M. Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain 2012;135:1554-1565.
7. Mesulam M-M, Dickerson BC, Sherman JC, Hochberg D, Gonzales RG, Johnson KA, Frosh MP. Case 1-2017: A 70 year-old woman with gradually progressive loss of language. New Eng J Med 2017;376:158-167.
8. Kim G, Ahmadian SS, Peterson M, Parton Z, Memon R, Weintraub S, Rademaker A, Bigio E, Mesulam M-M, Geula C. Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions. Neurology 2016;86:627-636.
9. Kim G, Bolbolan K, Gefen T, Weintraub S, Bigio E, Rogalski E, Mesulam M-M, Geula C. Atrophy and microglial distribution in primary progressive aphasia with transactive response DNA-binding protein-43 kDa. Ann Neurol 2018.
10. Gitelman DR, Nobre AC, Sonty S, Parrish TB, Mesulam M-M. Language network specializations: An analysis with parallel task design and functional magnetic resonance imaging. NeuroImage 2005;26:975-985.
11. Mesulam M-M, Rogalski E, Wieneke C, Cobia D, Rademaker A, Thompson C, Weintraub S. Neurology of anomia in the semantic subtype of primary progressive aphasia. Brain 2009;132:2553-2565.
12. Rogalski E, Cobia D, Harrison TM, Wieneke C, Thompson C, Weintraub S, Mesulam M-M. Anatomy of language impairments in primary progressive aphasia. J Neurosci 2011;31:3344-3350.
13. Mesulam M-M, Wieneke C, Hurley RS, Rademaker A, Thompson CK, Weintraub S, Rogalski EJ. Words and objects at the tip of the left temporal lobe in primary progressive aphasia. Brain 2013;136:601-618.
14. Mesulam M-M, Thompson CK, Weintraub S, Rogalski EJ. The Wernicke conundrum and the anatomy of language comprehension in primary progressive aphasia. Brain 2015;138.
15. Hurley RS, Paller K, Rogalski E, Mesulam M-M. Neural mechanisms of object naming and word comprehension in primary progressive aphasia. J Neurosci 2012;32:4848-4855.
16. Sonty SP, Mesulam M-M, Weintraub S, Johnson NA, Parrish TP, Gitelman DR. Altered effective connectivity within the language network in primary progressive aphasia. J Neurosci 2007;27:1334-1345.
17. Catani M, Mesulam M-M, Jacobsen E, Malik F, Martersteck A, Wieneke C, Thompson CK, Thiebaut de Schotten M, Dell’Acqua F, Weintraub S, Rogalski E. A novel frontal pathway underlies verbal fluency in primary progressive aphasia. Brain 2013;136:2619-2628.
18. Mesulam M-M. Primary progressive aphasia: a 25-year retrospective. Alzheimer Disease and Associated Disorders 2007;21:S8-S11.
19. Mesulam M-M, Rogalski E, Wieneke C, Hurley RS, Geula C, Bigio E, Thompson C, Weintraub S. Primary progressive aphasia and the evolving neurology of the language network. Nature Reviews Neurology 2014;10:554-569.
20. Mesulam M, Weintraub S. Is it time to revisit the classification of primary progressive aphasia? Neurology 2014;82:1108-1109.
21. Mesulam MM, Rader BM, Sridhar J, Nelson MJ, Hyun J, Rademaker A, Geula C, Bigio EH, Thompson CK, Gefen TD, Weintraub S, Rogalski EJ. Word comprehension in temporal cortex and Wernicke area: a PPA perspective. Neurology 2019;92:e224-e233.
22. Mesulam MM, Nelson MJ, Hyun J, Rader B, Hurley RS, Rademakers R, Baker MC, Bigio EH, Weintraub S. Preferential disruption of auditory word representations in primary progressive aphasia with the neuropathology of FTLD-TDP type A. Cognitive and Behavioral Neurology 2019;32:46-53.

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.

1. Mesulam M-M. Neuroplasticity failure in Alzheimer’s disease: Bridging the gap between plaques and tangles. Neuron 1999;24:521-529.
2. Guillozet AL, Weintraub S, Mash DC, Mesulam M-M. Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Arch Neurol 2003;60:729-736.
3. Geula C, Mesulam M-M. Cortical cholinergic fibers in aging and Alzheimer’s disease: a morphometric study. Neuroscience 1989;33:469-481.
4. Emre M, Heckers S, Mash DC, Geula C, Mesulam M-M. Cholinergic innervation of the amygdaloid complex in the human brain and its alterations in old age and Alzheimer’s disease. J Comp Neurol 1993;336:117-134.
5. Mesulam M-M, Shaw P, Mash D, Weintraub S. Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann Neurol 2004;55:815-828.
6. Mesulam M-M. The cholinergic lesion of Alzheimer’s disease: pivotal factor or side show? Learning & Memory 2004;11:43-49.
7. Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam M-M. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Age 2007;28:327-335.
8. Mesulam M-M, Geula C, Morán A. Anatomy of cholinesterase inhibition in Alzheimer’s disease: Effect of physostigmine and tetrahydroaminoacridine on plaques and tangles. Ann Neurol 1987;22:683-691.
9. Wright CI, Geula C, Mesulam MM. Neuroglial cholinesterases in the normal brain and in Alzheimer’s disease: relationship to plaques, tangles, and patterns of selective vulnerability. Ann Neurol 1993;34:373-384.
10. Mesulam M-M, Guillozet A, Shaw P, Levey A, Duysen EG, Lockridge O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 2002;110:627-639.
11. Rogalski E, Sridhar J, Rader B, Martersteck A, Chen K, Cobia D, Thompson C, Weintraub S, Bigio E, Mesulam M-M. Aphasic variant of Alzheimer’s disease: clinical, anatomic and genetic features. Neurology 2016;87:1337-1343.
12. Rogalski E, Rademaker A, Helenewski I, et al. APOE e4 is a susceptibility factor in amnestic but not aphasic dementias. American Journal of Alzheimer’s Disease and Other Dementias 2011;25:159-163.
13. Mesulam MM. Involutional and developmental implications of age-related neuronal changes: in search of an engram for wisdom. Neurobiol Aging 1987;8:581-583.
14. Mesulam M-M. Aging, Alzheimer’s disease, and dementia: Clinical and neurobiological perspectives. In: Mesulam M-M, ed. Principles of Behavioral and Cognitive Neurology, 2 ed. New York: Oxford University Press, 2000: 439-522.
15. Daffner KR, Scinto LF, Weintraub S, Guinessey JE, Mesulam MM. Diminished curiosity in patients with probable Alzheimer’s disease as measured by exploratory eye movements. Neurology 1992;42:320-328.
16. Rogalski E, Gefen T, Shi J, Samimi M, Bigio E, Weintraub S, Geiula C, Mesulam M-M. Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging project. J Cog Neurosci 2013;25:29-36.

1. Mesulam MM, Perry J. The diagnosis of love-sickness: experimental psychophysiology without the polygraph. Psychophysiology 1972;9:546-551.
2. Mesulam M-M. Dissociative states with abnormal temporal lobe EEG. Multiple personality and the illusion of possession. Arch Neurol 1981;38:176-181.
3. Mesulam MM. Schizophrenia and the brain [editorial]. N Engl J Med 1990;322:842-845.
4. Mesulam M-M. Higher visual functions of the cerebral cortex and their disruption in clinical practice. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Philadelphia: Saunders, 1994: 2640-2653
5. Mesulam MM, Geschwind N. Disordered mental states in the postoperative period. Urol Clin North Am 1976;3:199-215.
6. Mesulam M-M. Frontal cortex and behavior. Ann Neurol 1986;19:320-325.
7. Sandson TA, Daffner KR, Carvalho PA, Mesulam MM. Frontal lobe dysfunction following infarction of the left-sided medial thalamus. Arch Neurol 1991:48:1300-1303
8. Mesulam M-M. The human frontal lobes: Transcending the default mode through contingent encoding. In: Stuss D, Knight R, eds. Principles of Frontal Lobe Function. New York: Oxford University Press, 2002.
9. LaBar KS, Gitelman DR, Parrish TD, Mesulam M-M. Neuroanatomic overlap of working memory and spatial attention networks: a functional fMRI comparison within subjects. NeuroImage 1999;10:695-704.
10. Price BH, Daffner KR, Stowe RM, Mesulam MM. The comportmental learning disabilities of early frontal lobe damage. Brain 1990;113:1383-1393.
11. Weintraub S, Mesulam MM. Developmental learning disabilities of the right hemisphere. Emotional, interpersonal, and cognitive components. Arch Neurol 1983;40:463-468.
12. LaBar KS, Gitelman DR, Parrish TB, Kim Y-H, Mesulam M-M. Hunger selectively modulates corticolimbic activation to food stimuli in humans. Behavioral Neuroscience 2001;115:493-500.
13. Mohanty A, Gitelman DR, Small DM, Mesulam M-M. The spatial attention network interacts with limbic and monoaminergic systems to modulate motivation-induced attention shifts. Cereb Cortex 2008;18:2604-2613.

1. Mesulam, M-M. Neural Substrates of Behavior: The Effects of Focal Brain lesions upon Mental State. In: Nicholi AM, ed. The Harvard Guide to Psychiatry. 3^rd ed. Cambridge (MA): The Belknap Press of Harvard University Press; 1988. p. 101-133.
2. Mesulam, M-M. Aphasia, Memory Loss, Hemispatial Neglect, Frontal Syndromes, and Other Cerebral Disorders. In: Jameson JL, et al. Harrison’s Principles of Internal Medicine. 20^th ed. New York: McGraw-Hill; 2018. p. 1-9.