NOREPINEPHRINE is found in appreciable amounts in mammalian brain tissue. VOGT (1954) showed that this amine was unequally distributed in various regions of the cat brain, the highest concentrations being found in the hypothalamus. Similar findings were reported for other animal species (BERTLER and ROSENGREN, 1959a; MCGEER, MCGEER and WADA, 1963) and man (SANO, GAMO, KAKIMOTO, TANAGUCHI, TAKE~ADA and NISHINUMA, 1959). Dopamine is also present in the brain in comparable amounts to norepinephrine (MONTAGU, 1957 ; CARLSSON, LINDQVIST, MAGNUSSON and WALDECK, 1958) but with a different regional distribution, the highest concentrations being in the corpus striatum of both animals and man (BERTLER and ROSENGREN, 1959a; SANO et al., 1959; EHRINGER and HORNYKIEWICZ, 1960; BERTLER, 1961). The anatomical distribution of these two catecholamines in the brain was confirmed by the use of fluorescent histochemical techniques which allow a precise description of the cellular localization of the amines in brain tissue (CARLSSON, FALK and HILLARP, 1962; DAHLSTROM and FUXE, 1964; FUXE, 1965). These techniques revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system. The metabolism of catecholamines in the rat brain was studied by introducing small amounts of radioactive norepinephrine or dopamine directly into the lateral ventricle (MILHAUD and GLOWINSKI, 1962, 1963; GLOWINSKI, KOPIN and AXELROD, 1965; GLOWINSKI, IVERSEN and AXELROD, 1966). By this approach the blood-brain barrier to catecholamines can be circumvented, penetration of the radioactive catecholamines into the brain being allowed. The disposition of PHInorepinephrine in the whole brain indicates that [3H]norepinephrine introduced into the lateral ventricle of the brain mixes with the endogenous amine and can be used as a tracer to study the biochemical behaviour of norepinephrine in the brain (GLOWINSKI and AXELROD, 1966). PHIDopamine, which is also taken up and retained in the brain, is rapidly metabolized and converted to norepinephrine (GLOWINSKI et a!., 1966). The unequal regional distribution of the endogeneous catecholamines in the brain led us to undertake a study of the disposition of radioactive norepinephrine and dopamine in various brain regions after intraventricular injection. The regional

Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain.

The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.

Stereotaxic mapping of the monoamine pathways in the rat brain.

The sections in this article are:


1
Essence of Prefrontal Function: Regulation of Behavior by Representational Knowledge
11
Subdivisions of Prefrontal Cortex

12
Global Nature of Prefrontal Syndrome in Humans

13
Animal Model for Prefrontal Function in Humans

14
Delayed-Response Tests and Varying Interpretations of Their Functional Significance

15
Distractability and Perseveration: Secondary Consequences of Basic Defect in Representational Memory

16
Representational Memory in Wisconsin Card Sort and Other Diagnostic Tests of Prefrontal Function in Humans

17
Localization of Delayed-Response Function: Principal Sulcus

18
Circuit Basis of Visuospatial Functions




2
Accessing and “On-Line” Processing of Representations in Visuospatial Domain: Parietal-Prefrontal Connections
21
Visuospatial Representational Memory in Humans

22
Spatial-Mnemonic Nature of Delayed-Response Deficit: Domain-Specific Memory Loss

23
Topography of Representational Memory in Prefrontal Cortex

24
Electrophysiological Evidence of Spatial-Mnemonic Processes in Principal Sulcus

25
Parietal-Prefrontal Connectivity

26
Columnar and Laminar Framework for Feedforward and Feedback Mechanisms

27
Functional Significance of Parietal-Prefrontal Collaboration




3
Long-Term Memory and “Off-Line” Processing: Prefrontal-Limbic Connections
31
Role of Hippocampus in Spatial Memory

32
Multiple Connections Between Principal Sulcus and Hippocampal Formation

33
Quadripartite Neural Network: Parietal-Temporal-Cingulate-Prefrontal Circuit

34
Limbic Contribution to Spatial Memory




4
Response Initiation and Inhibition: Projections to Striatum, Tectum, Thalamus, and Premotor Cortex
41
Motor-Control Functions of Prefrontal Cortex

42
Cortical-Striatal Pathway and Related Feedback Loops

43
Cortical-Tectal Pathway

44
Thalamic-Cortical Systems

45
Prefrontal-Premotor Connections: Anterior Supplementary Motor Cortex Relays

46
Functional Speculations




5
Modulatory Mechanisms: Brain Stem Catecholamine Projections
51
Activation of Cognitive Machinery

52
Concentration and Synthesis of Catecholamines in Primate Cortex

53
Brain Stem Innervation of Prefrontal Cortex

54
Delayed-Response Deficits and Recovery Produced by Catecholamine Loss and Replacement in Prefrontal Cortex

55
Circuit Basis for Neuromodulation in Principal Sulcus




6
Multiple Subsystems of Prefrontal Cortex: Unity or Diversity of Function
61
Unity or Diversity of Prefrontal Function

62
Frontal Eye Fields

63
Inferior Convexity

64
Orbital Prefrontal Cortices

65
Problem of Integration




7
Diseases Affecting Prefrontal Cortex
71
Schizophrenia: Loss of Corticocortical Processing and Regulation of Behavior by Representational Knowledge

72
Wernicke-Korsakoff Syndrome: Loss of Thalamocortical and Brain Stem Modulatory Mechanisms

73
Huntington's Chorea and Parkinson's Disease: Loss of Prefrontal-Striatal Mechanisms and Initiation or Inhibition of Motor Response

74
Overview of Neurobiology of Disease




8
Summary

Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representational Memory

Some functions of gaze direction in social interaction

Part two of this three-part series commences with anomalous dominance and special talents. Part one appears in a previous issue of theArchives. 1 ANOMALOUS DOMINANCE AND SPECIAL TALENTS According to our hypothesis, slowed growth within certain zones of the left hemisphere is likely to result in enlargement of other cortical regions, in particular, the homologous contralateral area, but also adjacent unfaffected regions. The influences that favor anomalous dominance may thus favor talents associated with superior development of certain regions either in the right hemisphere or in adjacent parts of the left hemisphere. Even with excessive retardation of growth and the resultant migration abnormalities and learning disorders (LD), high talents may exist as a result of compensatory enlargement of other cortical regions. Several types of data are in concordance with these conclusions. Several studies have claimed that the average level of spatial talents is higher in male subiects. 2 Hier

https://jamanetwork.com/journals/jamaneurology/articlepdf/584161/archneur_42_5_008.pdf

Cerebral lateralization. Biological mechanisms, associations, and pathology: II. A hypothesis and a program for research.

Morphological asymmetry of the frontal operculum and temporal planum becomes measurable at the 29th week of gestation. There is evidence of subsequent differential development of the planum in favor of the left, with the left planum larger than the right. While both the frontal operculum and left planum were always present, the right planum ranged in size from absent (10%)to larger than the left (about 10%). Females predominated (P less than .05) in the latter group. The findings suggest that (1) a higher percentage of persons may have right-sided cerebral representation for speech than has been assumed previously; (2) a predetermined morphological asymmetry contributes to establishing the ultimate pattern of cerebral speech representation following an early insult to a predisposed hemisphere; and (3) it is necessary to scrutinize clinical material for the differential organization of hemispheric development between sexes.

Cerebral hemispheric asymmetry in humans. Cortical speech zones in 100 adults and 100 infant brains

Daily electrical stimulation of the amygdala in cats resulted in the progressive development of seizures through six distinct and sequential stages, culminating in a generalized convulsive seizure within an average of 25.5 days. On completion of the kindling, the generalized seizure-triggering threshold was within 100 to 300 μa, showing an all-or-none property. Electrographically, such seizure development was characterized by early distant propagation, amplitude growth of after-discharge, and development of interictal discharge along the ex-trapyramidal pathways through three distinct steps in which the mid-brain reticular formation plays a vital role in producing widespread secondary alteration and reorganization of brain function.

Generalized convulsive seizures induced by daily electrical stimulation of the amygdala in cats: Correlative electrographic and behavioral features

Summary

Daily unilateral electrical stimulation of initially subconvulsive amygdala resulted in progressive development of seizures (kindling) in cats, culminating in generalized convulsive seizures of focal onset that could occur spontaneously. Kindled cerebral epileptogenicity persisted for up to 12 months and was characterized by (1) interictal spike discharges of consistent morphology and localization, and (2) an “all or none” response to stimulation at the generalized seizure triggering threshold. Pentylenetetrazol (Metrazol) enhanced the frequency of interictal discharge without changing its localization or morphology, and caused generalized seizures with focal onset exactly like those produced by unilateral stimulation of the amygdala. These findings indicate that repeated electrical stimulation of amygdala produces widespread alteration of brain function resulting in a permanent state of epileptogenicity. Kindling thus qualifies as an experimental model reminiscent of certain types of human epilepsy.



REsume

La stimulation electrique quotidienne de l'amygdale qui etait initialement subconvulsive donnait lieu progressivement a des crises (“sensibilisation,” kindling) aboutissant a des crises convulsives a debut focal secondairement generalisees, et pouvant survenir spontanement. Cet etat de sensibilisation cerebrale predisposant a l‘epilepsie, persiste jusqu’a 12 mois et se caracterise (1) par des decharges intercritiques de pointes de morphologie et localisation constantes, et (2) par une reponse de type “tout ou rien”a une stimulation seuil declenchant des crises generalisees. Le pentylenetetrazol (Metrazol) augmente la frequence des decharges de pointes intercritiques sans toutefois modifier leur topographie et leur morphologie et provoque des crises a debut focal avec generalisation secondaire exactement identiques a celles produites par la stimulation unilaterale de l'amygdale. De telles donnees indiquent que des stimulations electriques repetees de l'amygdale produisent une alteration cerebrale diffuse, responsable d'un etat permanent d‘epileptogenicite. Cet etat (“kindling”) se pose done comme un modele experimental qui rappelle certaines formes d’epilepsie chez I'homme.



RESUMEN

La estimulacion electrica unilateral de una amigdala, previamente subconvulsiva, produjo el desarrollo progresivo de ataques en gatos, culminando en ataques generalizados de comienzo focal, que podian ocurrir espontaneamente. Este tipo de epileptogenesis “provocada” (“kindling”= eneender) persiste hasta 12 meses y se caracteriza por (1) descargas interictales de puntas de morfologia y localizacion persistente, y (2) una respuesta “todo o nada” con estimulacion a umbrales que desencadenan ataques generalizados. El pentilenetetrazol (Metrazol) aumento la frecuencia de interictales de puntas sin modificar su localizacion o morfologia y produjo ataques generalizados de comienzo focal identicos a los producidos por estimulacion unilateral de la amigdala. Estos hallazgos indican que la estimulacion repetida de la amigdala produce alteraciones diseminadas de la funcion cerebral que se traducen en un estado permanente de epileptogenesis. Asi pues, “kindling” representa un modelo experimental aceptable que recuerda ciertos tipos de epilepsyia humana.



ZUSAMMEnfassung

Tagliche einseitige elektrische Stimulation des Amygdalon, die anfangs unterhalb der Krampfschwelle lag, fuhrte zur allmahlichen Ausbildung von Krampfen (“kindling”– Krampfbahnung, triggerung) bei Katzen. Sie kulminierten in generalisierten Krampfen mit fokalem Beginn, die auch spontan auftreten konnten. Die so aufgeschaukelte cerebrale Anfallsbereitschaft hielt bis zu 12 Monate an. Sie ist durch folgende Befunde charakterisiert: (1) Interiktale spike-Entladungen gleichbleibender Morphologie und Lokalisation; (2) “Alles oder Nichts”– Antwort auf Stimulation im Bereich der Schwelle fur die Auslosung generalisierter Anfalle. Pentylentetrazol (Metrazol) verstarkte die Haufigkeit der Interiktale spike-Entladungen, ohne dass sich ihre Lokalisation oder Morphologie anderte und verursachte generalisierte Krampfe mit fokalem Beginn, die genau denen glichen, die durch einseitige Stimulation des Amygdalon hervorgerufen werden konnten. Die Befunde sprechen dafur, dass wiederholte elektrische Stimulation des Amygdalon eine ausgedehnte Veranderung der Hirnfunktion hervorrufen kann, die in einem anhaltendem Zustand der Anfallsbereitschaft resultiert. Das “kindling,” die Anfallsbahnung durch repetitive elektrische Stimulation, zeight sich damit als experimentelles Modell, das an bestimmte Typen der Epilepsie beim Menschen erinnert.

Persistent Seizure Susceptibility and Recurrent Spontaneous Seizures in Kindled Cats

SUMMARY

Daily unilateral electrical stimulation of amygdala in forebrain bisected cats provoked the development of the final stage of the kindled convulsion with remarkable rapidity regardless of presence or absence of anterior commissure. The chronological and spatial pattern of propagation of afterdischarge, interictal spike discharge, and clinical manifestations strongly suggest the significant role played by the midbrain reticular formation and possibly other brainstem structures in the progressive electroclinical seizure development. This assumption was supported by the results of a lesion study in which placement of a destructive lesion in the ipsilateral midbrain reticular formation markedly increased the generalized seizure triggering threshold, later-alized the afterdischarge to the stimulated hemisphere when induced with increased intensity stimulation, fragmented clinical seizure manifestations, and failed to produce progression of clinical and electrographic events with prolonged daily stimulation. This is in contrast to the insignificant effect produced by a peduncular lesion. Our findings suggest that vertical (limbic-brainstem), but not horizontal (transhemispheric interlimbic) connection is critically involved in the amygdaloid seizure development while the forebrain commissures may play a role in the development of bisynchronous and bisymmetrical ictal and interictal electrographic and clinical manifestations. Finally, possible differential effect of forebrain bisection depending on developing in contrast with an established (cerebral) hemispheric epileptogenic process is postulated to explain the “facilitatory” effect observed in our series in contrast to the beneficial effects reported on some intractable seizure patients.



RESUME

Une stimulation electrique journaliere de l'amygdale dans l'encephale anterieur bisseque de chats, provoque une evolution de l‘etat final de la convulsion excitee remarquablement rapide, sans considerer la prence ou l'absence de commissure anterieure. Le mode de propagation chronologique et spatial de apres-decharge, “interictal spike decharge” et les manifestations cliniques indiquent clairement le role vital joue par formation reticulaire du mesencephale et peut-etre d'autre structures pedonculaire du cerveau dans le developpement de l'etat final de l'attaque. Cette hypothese est soutenu par les resultats de l'etude d'une lesion, dans laquelle 1'introduction d'une lesion de-structriace dans la formation reticulaire homo-laterale du meencephale augmente remarquablement le seuil de l'attaque, bloque l'apparence d'une attaque generalised, et lateral-ise Papresdecharge dans Phemisphere stimule. Ceci contraste avec l'effet insignificant produit par une lesion pedonulaire. Nos recherches suggerent que le renforcement de 1'attache due pedoncle limbique du cerveau (formation reticulaire du mesencfiphale) est d'une importance decisive pour le phenomene d'excitation pendant que la commissure du “forebrain” joue un role dans le developpement electrographique et clinique des manifestations bisynchronique et bisymetrique, “ictal” et “inter-ictal.” Enfin, un effet differenciel possible de la bissection du prosencephale, celon le development du procede compare a celui hemispherique (cerebral) epileptogene connu, est suggere pour expliquer l'effet de “frayage” (facilitatory) observe dans nos serie d'experiences en contraste avec les effets salutaires relates chez quelques malades critiques intraitables.



RESUMEN

La estimulacidn electrica diaria de la arm'gdala en gatos produce un desarrollo progresivo de ataques electroclinicos que culminan en convulsiones generalizadas (Kindling).



Una lesion electrolftica en la sustancia reticular mesencefalica, homolateral a la amfgdala estimulada, produjo una marcada elevacion del umbral para convulsiones generalizadas y redujo la susceptibilidad al pentilen-tetrazol. Por el contrario lesiones en el palido no produjeron efectos sobre el umbral convul-sivo y dieron la impresion de aumentar la susceptibilidad al pentilentetrazol.



Estos resultados apoyan la hipotesis de que: (1) la sustancia reticular mesencefalica participa de manera significativa en el proceso del progresivo desarrollo de convulsiones amigdalo-ideas, y (2) los efectos de las lesiones en la sustancia reticular mesencefalica no dependen de la presencia de la bisection del telencefalo.



ZUSAMMENFASSUNG

Tagliche elektrische Reizung des Mandel-kerns verursacht bei Katzen Auftreten und Zunahme elektro-klinischer Anfalle, die in generalisierten Konvulsionen gipfeln (“kindling”– Aufschaukelphanomen). Eine elek-trolytbedingte Lasion der Formatio reticularis im Mittelhirn, auf der Seite des gereizten Mandelkerns erhoht deutlich die Reizschwelle fur die Auslosung generalisierter Anfalle und vermindert die Empfindlichkeit gegeniiber Pen-tylentetrazol. Im Gegensatz dazu zeigen Verlet-zungen des Globus pallidus keinen verwertbaren Effekt auf die Ausloseschwelle fur generalisierte Krampfanfalle. Sie scheinen die Empfindlichkeit gegenuber Pentylentetrazol zu erhohen.



Diese Ergebnisse unterstiitzen folgende Hypothesen:



1
Die Formatio reticularis des Mesencephalon spielt eine wesentliche Rolle im Prozess der Entwicklung und Auspragung von Anfallen ausgehend vom Mandelkern.

2
Die Auswirkung einer Lasion in der Formatio reticularis des Mittelhirns ist nicht abhangig von einer Unterbrechung der Verbin-dung zum Telencephalon.

Juhn A. Wada

Papers

Cerebral hemispheric asymmetry in humans. Cortical speech zones in 100 adults and 100 infant brains

Generalized convulsive seizures induced by daily electrical stimulation of the amygdala in cats: Correlative electrographic and behavioral features

Persistent Seizure Susceptibility and Recurrent Spontaneous Seizures in Kindled Cats

The generalized convulsive seizure state induced by daily electrical stimulation of the amygdala in split brain cats.

Potentiation of amygdaloid kindling and metrazol-induced seizures by 6-hydroxydopamine in rats.