Journal of the American Medical Informatics Association Volume 15 Number 5 September / October 2008 671

Model Formulation Ⅲ Modeling Functional Neuroanatomy for an Anatomy Information System

JÖRG M. NIGGEMANN, MD, DIPL INFORM,ANDREAS GEBERT, MD, STEFAN SCHULZ,MD

Abstract Objective: Existing neuroanatomical ontologies, databases and information systems, such as the

Foundational Model of Anatomy (FMA), represent outgoing connections from brain structures, but cannot represent Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021 the “internal wiring” of structures and as such, cannot distinguish between different independent connections from the same structure. Thus, a fundamental aspect of Neuroanatomy, the functional pathways and functional systems of the brain such as the pupillary light reflex system, is not adequately represented. This article identifies underlying anatomical objects which are the source of independent connections (collections of neurons) and uses these as basic building blocks to construct a model of functional neuroanatomy and its functional pathways. Design: The basic representational elements of the model are unnamed groups of neurons or groups of neuron segments. These groups, their relations to each other, and the relations to the objects of macroscopic anatomy are defined. The resulting model can be incorporated into the FMA. Measurements: The capabilities of the presented model are compared to the FMA and the Brain Architecture Management System (BAMS). Results: Internal wiring as well as functional pathways can correctly be represented and tracked. Conclusion: This model bridges the gap between representations of single neurons and their parts on the one hand and representations of spatial brain structures and areas on the other hand. It is capable of drawing correct inferences on pathways in a nervous system. The object and relation definitions are related to the Open Biomedical Ontology effort and its relation ontology, so that this model can be further developed into an ontology of neuronal functional systems. Ⅲ J Am Med Inform Assoc. 2008;15:671–678. DOI 10.1197/jamia.M2358.

Introduction ties, neurons, which are considered its functional units. In Functional Anatomy is concerned with anatomical entities textbook illustrations they are usually visualized as blobs. grouped together to perform a physiological function. In In the text, however, adequate expressions such as “a Functional Neuroanatomy, a typical example is the visual collection of neurons within the lateral geniculate body system. Neuroanatomy textbooks are usually illustrated projects to a collection of neurons within area 17” are with drawings similar to the ones in Figure 1 which exhibit unusual. Such expressions are precise, but clumsy. Instead, an important peculiarity of Functional Neuroanatomy: the the same scenario is expressed as “the lateral geniculate main focus is not on single anatomical entities, such as in the body projects into the area 17.” This compromise, however, musculoskeletal system, but on collections of uniform enti- obscures some detail—especially when the anatomical enti- ties being described are constituted, in reality, by several qualitatively different collections of neurons. Affiliations of the authors: Klinikum rechts der Isar, Technical A symbolic representation of anatomy—especially for di- University of Munich (JMN), Munich, Germany; Institute of Anat- dactic purposes—should represent facts on a comprehensi- omy, University of Lübeck (AG), Lübeck, Germany; Institute of Medical Biometry und Medical Informatics, Freiburg University ble, but detailed level, and yield output on the level of object Medical Center (SS), Freiburg, Germany. names. To this end, we here diligently define both levels, and establish the transition rules between them. The model Dr Niggemann is currently with CompuGROUP Holding AG, Koblenz, Germany. presented here is derived from an approach that had been implemented in the early anatomy e-learning system “Ana- The authors thank Dr. Reinhard Eggers (Department of Anatomy, tom-Tutor”1 and is put into the context of current ontologies University of Luebeck) for valuable discussions of neuroanatomical details. The groundwork for this article was partly funded by a such as the Foundational Model of Anatomy (FMA). fellowship of Deutsche Forschungsgemeinschaft (DFG) and by the German Ministry of Science and Technology (BMFT) under contract Background ITW 9106. The authors also thank the anonymous reviewers for valuable discussions and hints. Representations of Anatomy and Neuroanatomy Correspondence: Dr. Jörg Niggemann, CompuGROUP Holding and Their Respective Focus AG, Maria Trost 21, D-56070 Koblenz, Germany; e-mail: Ͻjoerg. The organization of the nervous system of various species is Ͼ [email protected] . currently represented in several large systems. NeuroNames is Received for review: 12/29/06; accepted for publication: 05/04/08. a nomenclature of human and macaque brain structures, 672 Niggemann et al., Modeling Functional Neuroanatomy Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021

Figure 1. A. Pupillary light reflex (crossover connections not shown). a: group of neuron cell bodies in the retina. b: group of axons. c: branching of the axons. d: branch leading to the pretectal nucleus. e: connection to a group of cell bodies in the parvocellular oculomotor nucleus. f: fibers running in the oculomotor nerve. g: connection to a group of cell bodies in the ciliary ganglion. h: termination in the sphincter muscle of iris. B. Accommodation reflex (crossover connections not shown). a: group of neuron cell bodies in the retina. b: group of axons. c: connection in the lateral geniculate body. d: connections within the area-17, and subsequent connection to a group of cell bodies in the pretectal nucleus. e: connection to a group of cell bodies in the parvocellular oculomotor nucleus. f: fibers running in the oculomotor nerve. g: connection to a group of cell bodies in the ciliary ganglion. h: termination in the ciliary muscle. C. The pathways combined. An anatomy information system must represent at least all the information illustrated in this picture: Two different pathways involving different groups of neurons in the pretectal nucleus, the parvocellular oculomotor nucleus and the ciliary ganglion. 1: nasal half of the right retina. 2: temporal half of the right retina. 3: optic nerve. 4: optic chiasm. 5: optic tract. 6: lateral geniculate body. 7: Brodmann area 17 (area striata, primary visual cortex). 8: pretectal nucleus. 9: parvocellular oculomotor nucleus. 10: ciliary ganglion. 11: ciliary muscle. 12: sphincter muscle of iris. All drawings by the authors in the style of textbook illustrations. designed as a tool for indexing digital databases of neurosci- roanatomy, viz. functional neuroanatomy, which is con- entific information. It was started in the late 80’s as a cerned with pathways and systems, can not readily be MacIntosh hypercard stack2 and has since been developed represented in the FMA in its current form. 3 into a web-accessible database. Its primary objects are 9 4 Brain Architecture Management System (BAMS) and anatomical entities identified by names. Brainmaps.org10 are web accessible repositories and digital The Foundational Model of Anatomy (FMA)5 is a frame- atlases on neuroanatomy, containing each a compilation based ontology, originally designed to represent the macro- from different atlases and for different species. Both contain scopic anatomy of the human thorax. It was assumed that data on connections, and in both, like in the FMA, collaterals this would cover all complexities of anatomy, and in this can not be distinguished from axons originating in different way the model could later be easily extended to other body neuron populations. areas and to other granularity levels such as cellular and Other web accessible anatomy information resources: Kim subcellular structures. When incorporating neuroanatomy et al. have recently conducted a review of 40 online re- from NeuroNames, the authors themselves encountered sources on anatomy,11 most of them aimed at education. Six diverse problems with this approach.6–8 The Foundational of them are dedicated to Neuroanatomy, four of which still Model was further enhanced to accommodate so-called in service (see Table A1 in the online appendix, available at input/output relationships in order to represent the flow of http://www.jamia.org). None of them contains explicit in- information through the nervous system. The corresponding formation on functional systems. Other recent neuroanat- slots “Gets Input From” and “Sends Output To” are, how- omy teaching systems are Brain Project/3D-Brain 2.012 and ever, not restricted in terms of domain and range con- 13 straints. For example, the class “organ region” has this slot. BrainTrain. Like the other resources cited above, these do Most neuroanatomical objects are listed under this class, but not represent neural connections in functional systems. also others such as “auricle of heart” and “segment of In summary, the aforementioned neuroanatomical systems tooth.” Furthermore, it is not distinguishable whether two address nomenclature, hierarchical taxonomy, part-of hierar- connections which an object exhibits are collaterals or chy, connections, cytoarchitecture, and different mappings whether they originate in different populations of neurons of the cortex. In all of them the primary objects of represen- within the object. Therefore, an important subfield of neu- tation are macroscopic, morphologically-defined anatomical Journal of the American Medical Informatics Association Volume 15 Number 5 September / October 2008 673 structures. Their main disadvantage is their inability to well as groups of neuronal cell bodies and groups of represent internal subgroups of neurons and their connec- neuronal axons with their myelin sheaths. tions, the “internal wiring” of neuroanatomical objects. Model Formulation Formal Ontologies Both terms and relations in an ontology have to be well- The model we are proposing addresses specific aspects of defined so that automated reasoning becomes feasible and Neuroanatomy. This model is meant to be useful under yields meaningful results (see Smith et al., 2005).14 Recently many perspectives: both on an instance (token, individual, the Open Biomedical Ontologies (OBO) consortium has particular) and a class (type, concept, universal) level, and— compiled the OBO ontology library, a repository of con- from a philosophical perspective—both under a “conceptu- trolled vocabularies developed for shared use across differ- alist” and a “realist” point of view. The model of anatomical ent biological and medical domains. Smith et al.14 reviewed groups is introduced in an atemporal way, as we intend to the definition and use of relations in these ontologies and model one idealized, prototypical, “normal” instance of a human nervous system at one specific point in time. This is found, that even the most basic relations part-of and is-a are Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021 not always used in consistent fashion both within and the perspective taken e.g., in anatomical atlases, which between ontologies. The authors then proceeded to define introduce general “classes” such as “flat bone” but then an “ontology of relations,”15 which we will use here as a describe every bone in the body as one instance of such a starting point. class. We introduce the terms group and individual with the relations has-member and member-of. From the OBO Defining Anatomical Objects as Counts, relations ontology15 we choose the following ones as primitive Collections, Mass, etc. relations in our model: part-of, located-in, adjacent, instance-of, The idea proposed in this paper is to define the basic is-a. (New terms which we introduce as names of classes/ concepts of functional neuroanatomy in terms of groups of universals are printed in small caps, such as Functional- uniform objects. This idea is related to the works of Bittner, Group. We consider relations netween instances only, they are Rector et al.,16–18 who suggested the description of the printed in italics.) relation between collectives of uniform objects and each of Analyzing the Underlying Structures their single constituents as has-granular-part, a subrelation of In order to express “groups of neurons” and “groups of has-part. neuron parts,” we start with a brief inspection of the Functional Anatomy underlying particulars, the neurons themselves. We do this Johansson et al.19 have introduced “pure structural anat- on the “cell” and “subcellular” levels of granularity. Here omy” and “pure functional anatomy” as perspectives on we look at a neuron and its relevant segments, and then anatomy. They argue that there are two ways to draw define the basic relations of adjacency and efference. After- boundaries between spatial parts of the body: structural and wards, we can transpose these definitions into the higher functional. About the functional parts the authors state: “A granularity level of groups, which lies between the “cell” part-of relation between such spatial-functional entities goes and the “tissue” granularity levels. parallel to a sub-function relation among the functions asso- Nerve cells (neurons) are the individual information proces- 20 ciated to the spatial-functional entities”. Niggemann out- sors of the neural system. Figure 2 depicts a typical neuron. lined a similar perspective with respect to neuroanatomy, It has a long process, the axon, which conducts electric from the point of view of knowledge representation. He signals to target cells (targets can be other neurons or argued that the spatial dimension is not even necessary in effectors such as muscle cells). Every axon is part of some order to define a “functional object” (however, this topic is neuron. Most axons are covered by a myelin sheath which beyond the scope of this article). consists of cells or parts thereof. An axon together with its myelin sheath is called a fiber. Fibers can be partitioned into Example: The Visual System segments according to the Ranvier’s nodes in the myelin Our model is introduced using the visual system as an sheath. The segment of a fiber between two nodes is called example. We concentrate on the reflex systems of the pupil- the internodal segment. The terminals of the fiber form part lary light reflex and the accommodation reflex (Fig 1). Both of the conducting connection to the target cell. The connec- reflex arcs involve a group of neurons in the parvocellular tion or synapse overlaps the source neuron as well as the oculomotor nucleus which send their signals (efferences) to target cell. The central part of the neuron which includes the a group of neurons in the ciliary ganglion (e, f, g in Figures cytoplasm, cell nucleus and the surrounding plasma mem- 1A and 1B). Important to note is that the two reflex arcs involve two different groups of neurons in the pretectal nucleus, the parvocellular oculomotor nucleus and the cili- ary ganglion. The sentence “The parvocellular oculomotor nucleus sends output to the ciliary ganglion” is correct in both reflexes, but this information alone is not sufficient to distinguish be- tween the two reflex arcs. We need a way to represent different connections within the structures, such as they are depicted in Fig. 1C. In general, we want to represent the Figure 2. Schematic depiction of a neuron. 1: cell body, 2: most detailed information available. For this purpose we axon, 3: schwann’s cell, 4: ranvier’s node, 5: branching of the introduce a model which represents groups of neurons, as axon, 6: terminals. 674 Niggemann et al., Modeling Functional Neuroanatomy

From NEURON-STRUCTURES to Groups Now the transition is made from Neuron-Structures to groups. To achieve this, we will define an equivalent in the group level for each object and each relation on the Neuron- Structure level (Fig. 3). We uniformly name all group objects with the postfix “-group”. Functional-Group is the common subsumer of all groups that can be derived from the Neuron-Structures defined above, together with groups of neurons themselves. It can be defined more generally by use of the criteria of a common connection pattern or participation in a common function. Fig. 4 shows a taxonomy of the classes defined in this

section. Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021 Definition (Functional-Group) A Functional-Group is a collection of neurons or neuron segments of the same type, such that: Figure 3. From cellular to group layer. 1: group of Cell Bodies: Cell-Body-Group 2: group of R-Segments: Atom- a) all members of the group share a common connection ic-Fiber-Segment-Group 3: group of sequences of R-Sec- pattern (they are recipients of input from the same source tions: Fiber-Segment-Group 4: group of Terminals: Termi- or have output/efference to the same target or any nal-Group 5: group of Fibers: Fiber-Group 6: group of combination thereof) complete Neurons: Neuron-Group. b) 1) all share a given location, or brane but excludes the axon, dendrites (see below) and any 2) the group as a whole is bearer of a (sub-) function, all other neurites is called the cell body. Many neurons also its members are capable of contributing to the group’s have dendrites: protuberances to which synapses connect function and which conduct the excitation to the cell body. In this c) the group contains (has-member) all individuals which functional model, it is irrelevant whether a terminal con- share these properties. nects to a dendrite or directly to the cell body, we therefore A Functional-Group is therefore a kind of “ObjectAggre- abstract from this detail. gate” as defined in the Basic Formal Ontology (BFO)21,22 as Definition (R-Segment,Fiber-Segment) “An independent continuant that is a mereological sum of separate objects and possesses non-connected boundaries”. The smallest functional segment of a fiber is an internodal segment together with its following node; we will give it the Similarly, the definition of Functional-Group is consistent 23 name R-Segment. We also need to define fiber segments of with Simons’ notation of “group.” arbitrary length: A Fiber-Segment is one R-Segment or a Relations between FUNCTIONAL-GROUPS sequence of connected R-Segments, possibly ended with a We define two sets of relations between Functional- terminal. Groups. One describes relations with respect to signal This definition is needed when we want to express the conduction, the other with respect to their members. meaning of sentences like: “The fibers originating in the retina run through the optic nerve”. This can be translated as “Each of the fibers has some Fiber-Segment as part which is spatially located-in the optic nerve”. Definition (Neuron-Structure) We define as Neuron-Structure all sections of a neuron introduced in the previous description and definition. Relations Between Neuron-Structures The relations between the cell-structure-level objects serve as an orientation for defining relations between group objects. Definition (Efferent-to, Afferent-to, Direct-efferent-to, Direct-afferent-to) Neuron-Structures pass electrical excitation: A Neuron-Structure is in relation efferent-to another one, if and only if it passes signals to it. Efferent-to is a transitive relation. Direct-efferent-to is a subrelation of efferent-to,it additionally requires spatial adjacency and therefore is not transitive. The same holds for the inverse, afferent-to and direct-afferent-to. A neuron is in relation direct-efferent-to another one, if and only if it has as a part a terminal, which is direct-efferent-to, the second neuron. Figure 4. Taxonomy of Functional-Group Classes. Journal of the American Medical Informatics Association Volume 15 Number 5 September / October 2008 675

Definition (Relations with Respect to Connections) The example used in the definition of Fiber-Segment can be The same relations that are defined for Neurons and Neu- reformulated using Fiber-Group: “The Fiber-Group origi- ron-Structures can be used between Functional- nating in the retina runs through the optic nerve”, with the Groups: interpretation that there is a Fiber-Segment-Group which is part of the Fiber-Group and which is spatially located-in the efferent-to/afferent-to: We define efferent-to as the transitive relation which represents signal passing. A Functional- optic nerve.

Group g1 is in relation efferent-to to another Functional- Definition (Group of terminals: Terminal-Group) Group g2 if and only if for every member m1 of g1 there is a Finally, Terminal-Group can naturally be defined as a member m2 of g2 such that m1 efferent-to m2.afferent-to is the inverse relation. group of terminals which belong to the same Fiber-Group and connect to the same target. direct-efferent-to/direct-afferent-to: Similarly, the non-transi- tive relations direct-efferent-to/direct-afferent-to can be derived The Level of Macroscopic Objects from the underlying Neuron-Structures: AFunctional- The goal for a readable output of an anatomy information Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021

Group g1 is in relation direct-efferent-to to another Functional- system is to transform the fact “The neural excitations which

Group g2 if and only if for every member m1 of g1 there is a contribute to the right pupillary light reflex are conducted member m2 of g2 such that m1 direct-efferent-to m2. direct- via cbg1, cbg2, cbg3...” (following efferent-to relations be- afferent-to is the inverse relation. tween Cell-Body-Groups) into the sentence: “. . . conducted Definition (Mereological Relations) via: right temporal retina, right lateral geniculate cor- pus, . . .”. That means we have to replace the unnamed subgroup-of: A Functional-Group g is subgroup-of another 1 Cell-Body-Groups with named anatomical objects. Functional-Group g2 if and only if every member of g1 is also member of g2. Thus the subgroup-of relation corresponds In order to make the transition from the level of groups to to a part-of relation between groups. the level of macroscopic, named anatomical objects, we need to define the kind of objects that are candidates for “named overlap: A Functional-Group g1 overlaps another Func- tional-Group g2 if and only if there is at least one member anatomical objects” in this context. of g1 which is also member of g2. Definition (Macroscopic-Neuroanatomical- equal: Two Functional-Groups are equal if and only if they Entity) have exactly the same members. A Macroscopic-Neuroanatomical-Entity is an object of sum: A Functional-Group g1 is sum of Functional-Groups neuroanatomy which g2 and g3 if and only if every member of g1 is also member of g2 or g3 and both g2 and g3 are subgroups of g1. 1. is visible to the human eye without the help of a microscope 2. occupies a connected space Subclasses of FUNCTIONAL-GROUP Definition (Group of Complete Neurons: Neuron- (An object occupies a connected space if for every two Group) spatial points A and B within the object there exists a path from A to B which is entirely in the object). A group of neurons will be called Neuron-Group. Relations of MACROSCOPIC-NEUROANATOMICAL-ENTITIES Definition (Group of Cell-Bodies: Cell-Body-Group) In the scope of this article, the only interesting relation A Cell-Body-Group is a group of cell bodies, all of which between Macroscopic-Neuroanatomical-Entities is share a common function or common connections. Therefore, part-of/has-part. As mentioned above, we consider this to be looking at functions and subfunctions or at connections in a primitive relation. different levels of granularity leads to different formations of We now define located-in as a relation between Functional- Cell-Body-Groups. Groups and Macroscopic-Neuroanatomical-Entities.We Definition (Group of Fibers: Fiber-Group) define the relation through the group’s members, whose loca- Fiber-Group refers to a group of complete fibers (axons with tion in the respective object can be microscopically verified. myelin sheath if applicable) from cell bodies to terminals. Definition (Located-in as Relation between Note that a complete fiber is a (maximal) Fiber-Segment, such that Fiber-Group must be considered a subtype of Functional-Group and Macroscopic- Fiber-Segment-Group. Neuroanatomical-Entity) On the group level like on the Neuron-Structure level we A Functional-Group g is located-in a Macroscopic-Neuro- need to define a smallest (functional) segment of a Fiber- anatomical-Entity m if and only if each member of g is Group. We derive this from the smallest (functional) seg- located-in m. ment of a fiber, the R-Segment. So we can define: Now we can proceed to reconstruct the FMA relation Definition (Group of R-Segments: sends-output-to between Macroscopic-Neuroanatomical-Enti- Atomic-Fiber-Segment-Group) ties. An Atomic-Fiber-Segment-Group is a group of parallel Definition (Receives-input-from, Sends-output-to) R-Segments within the same Fiber-Group. A Macroscopic-Neuroanatomical-Entity m1 sends-out- Definition (Group of Fiber-Segments: put-to another Macroscopic-Neuroanatomical-Entity m2 Fiber-Segment-Group) if and only if there are some Cell-Body-Groups f1, f2 such that f located-in m and f located-in m and f efferent-to f . A Fiber-Segment-Group is a collection of parallel Fiber- 1 2 2 1 2 Segments receives-input-from is the inverse. 676 Niggemann et al., Modeling Functional Neuroanatomy

Validation through Example Proof of Completeness, Correctness, Novelty and Advantage In this section we will prove that the Functional-Group model is a valid and useful extension to models such as the FMA or BAMS. We use the example of the visual system to illustrate the steps of the proof. Claim: Augmenting a current model such as the FMA with the Functional-Group model 1. does not lead to any loss in information or capabilities 2. adds functionality which these models currently do not have Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021

In order to prove that the Functional-Group model can indeed add functionality to current models, we choose the FMA as an example and take the following steps:

1. We show that the current FMA can be transformed into Figure 5. Two-step augmentation of FMA models by the Functional-Group enhanced format. Especially, we Functional-Group information.A. A situation as it occurs show that in the original FMA: macroscopic anatomical objects (FMA a) this process can be reverted, which proves that no classes) are linked by “Sends Output To” links. These links information is lost in the conversion (completeness) can (by design) not carry any additional information. b) the classes which are automatically added correctly B. Each “Sends Output To” link has been replaced by a reflect anatomical reality (correctness) Neuron-Group. This replacement can be done automati- cally. It does not yet add any information. C. The structure 2. We prove that in the Functional-Group enhanced of the new model allows collators to add Neuron-Groups FMA, additional information (namely internal wiring) and direct-efferent-to links between Terminal-Groups and can be stored Cell-Body-Groups in one macroscopic object. This way, a) which could not be stored in the original FMA (nov- different pathways can be kept apart. elty) b) which allows inferences that could not be drawn in – can only originate in a neuron cell body (resp Cell-Body- the original FMA (advantage) Group) – must be conducted by an axon (resp Fiber-Group), and The complete proof is given in the online appendix. Here we – can be delivered/transmitted only through a terminal outline the main steps. (resp Terminal-Group) 1. Transformation of the FMA UNCTIONALinto a -GF ROUP Therefore it is a valid conclusion that each “Sends Output enhanced format To” relation implies the existence of such structures, and it is The transformation mainly involves correct to represent them explicitly. 1. Augmentation of the class hierarchy by the classes de- In summary, we have shown that the Functional-Group fined in section IV enhanced FMA (with no additional information added) and 2. Processing of all “Sends Output To” links the original can be mutually transformed into each other. This proves claim 1, that no information is lost in the The result is illustrated in Fig. 5A and B: The information transformation process. Also we have shown that the en- contained in the former “Sends Output To” links (Fig. 5A) is hanced model correctly reflects anatomical reality. now represented by Functional-Groups contained in the 2. Adding new information objects and their efferent-to connections (Fig. 5B). The de- tailed proof also shows that the original information can be The Functional-Group enhanced FMA now allows colla- recovered from the extended form. The process corresponds tors to add new information which wasn’t possible in the to redefining the relation “Sends Output To” as in Definition original model. In this section we have to prove that the (receives-input-from, sends-output-to) in section IV. same information cannot be stored in the current FMA (novelty) and that it is useful (advantage). Completeness: As we have only added classes, nothing is lost in this step. The original information in the “Sends 1. “Internal wiring” Output To” links can be recovered, proving that no infor- In this step, decisive new information can be added which mation is lost. makes the Functional-Group model so effective. It is the Correctness: As outlined in section IV, the new classes by step from Fig. 5BtoFig. 5C: New Functional-Groups are design correctly reflect anatomical entities. Since the proce- added and new efferent-to links are established between dure introduces new objects (the individual Functional- Terminal-Groups and Cell-Body-Groups. Groups and their relations), we must prove that these reflect Novelty: By design of the FMA, internal connections within anatomical reality. It is a fundamental truth in neuroanat- an object cannot be represented. This is because connections omy, that every neuronal signal are not objects themselves, they are just attributes of the Journal of the American Medical Informatics Association Volume 15 Number 5 September / October 2008 677 macroscopic anatomical objects. In the extension however, Discussion the connections are represented by objects within the mac- The Functional-Group model has been designed to ad- roscopic anatomical objects (Functional-Groups) which dress the topology of neural connections as a specific aspect can again be linked to each other (direct-efferent-to). There- of Neuroanatomy. So far we have presented a basic form of fore, internal connections within a macroscopic anatomical the model. Three aspects need further attention: The usabil- object can only be represented in the extension. ity of the model with incomplete information, the specific Advantage: Representing internal connections is a basic step phenomenon of the cross-connection of pathways, and the for distinguishing known pathways from candidate path- addition of more aspects of neuronal connections such as the ways (see next paragraph). transmitters involved. 2. Known Pathways and Functional Systems Use with Incomplete Information, and Aggregation The Functional-Group extension allows one to distinguish of Scientific Results between complex known pathways and candidate path- The steps described in the section “Validation Through ways, and to represent complete functional systems such as Example” illustrate how incomplete information is handled: Downloaded from https://academic.oup.com/jamia/article/15/5/671/733389 by guest on 30 September 2021 the accommodation reflex system as in Fig. 1C. when embedded in a “host system” such as the FMA, it is Novelty: In current models such as FMA or BAMS, candi- first set up to reconstruct that system’s “Sends Output To” date pathways can be generated by recursively following information. That information is necessarily incomplete be- “Sends Output To” links. It is not guaranteed that these cause information about internal wiring is lacking. In this candidates represent any anatomical or physiological real- stage, candidate pathways are found by assuming links from ity. In contrast, the addition of the “internal wiring” of every incoming to every outgoing connection of an object. direct-efferent-to links between Terminal-Groups and Cell- When scientific results about internal connections become Body-Groups where these are known, allows the enhanced available, these can be added to the model as described in the model to discern different functional systems. step “Adding new information,” thus enabling the model to represent known pathways and distinguish those from candi- Advantage: Known pathways can be represented and can be date ones. searched and followed, and they can be discerned from candidate pathways. One of the most important kind of The Cross Connection of the Pathways entities in functional neuroanatomy, functional systems, can Bright light causes a constriction of the pupil but not now be represented. A detailed example of how the system simultaneously an accommodation reaction. However, look- follows a known pathway is given in section “Following ing at nearby objects also leads to a constriction of the pupil. pathways in the Functional-Group model versus FMA This observation is a subject matter of physiology and, as and BAMS” in the online appendix. such, not directly represented in a neuroanatomical model. Together with the general axiom that in the nervous system 3. “White matter” pathway information there is no function without connection, we can conclude The resulting pathway structures can also represent the path that “there is some connection from at least one Cell-Body- that a connection takes through “white matter” structures Group involved in the accommodation pathway to at least (those that primarily contain axons or parts thereof). Fig 1 one other that is involved in the pupillary reflex pathway”. shows the structures through which fibers from the retina This first-order logic statement can not be represented in the pass on their way to the lateral geniculate body (numbers Functional-Group model (nor can it be represented in one 3–5 in Fig. 1C). With the Functional-Group extension, this of the other models mentioned). As soon as it is known information is now explicitly represented so that an infor- which Macroscopic-Neuroanatomical-Entity contains mation system can output information like “fibers from the this cross connection, the situation can be modeled, for retina run through the optic nerve, the optic chiasm, and example by adding a collateral from an incoming connection the optic tract”. This is equivalent to the statement “each of belonging to the accommodation reflex to the Cell-Body- the Fibers has a Fiber-Segment as part which is spatially Group of the pupillary light reflex, or by establishing other located-in the optic nerve, the optic chiasm, and the optic internal wiring as the scientific results suggest. tract.” Details are given in the online appendix. Scope and Possible Extension: More Detailed Novelty: The “Continuous With” relation of the original Description of Signal Transmission FMA is not constrained to objects of neuroanatomy; it is also Apart from the visual system, this approach has been used to link blood vessels, tendons etc. Therefore, the “white successfully tested with representations of the vestibular matter” pathway information can only be correctly repre- system, the auditive system, the accessory optical system, sented using the Functional-Group extension. long corticofugal tracts of the motoric systems, the extrapy- Advantage: An anatomical information system containing ramidalmotoric system, the central limbic continuum, this information can be used to reason about and to teach ascending reticular tracts, efferent connections of the cere- structure-function relationships such as consequences of bellum and thalamo-cortical connections. lesions to white matter structures. In its basic form, as presented here, the model only repre- In summary, we have shown that the Functional-Group sents the “bare” connections from terminal to target cell. It extended FMA can store information and draw conclusions, does not represent dendrites, different kinds of synapses, or which the design of the original FMA does not allow. This different neurotransmitters. In a more advanced form, our proves claim 2 and completes the proof that the Func- model can be expanded to cover such details. The existing tional-Group model is a valid and useful extension of the objects can then be enriched with attributes such as “adren- FMA. ergic,” and new intermediate objects can be introduced 678 Niggemann et al., Modeling Functional Neuroanatomy between synapse and target cell bodies in order to represent 9. Bota M, Dong H, Swanson LW. Brain Architecture Management dendrites. Further extensions can express characteristics of System. Neuroinformatics. 2005;3(5):15–48. signal conduction in the fibers and modulations thereof by 10. Brainmaps [homepage on the internet]. Davis, California: Uni- axo-axonal synapses. versity of California Regents Davis campus; c2005–2006 [up- dated 2007; cited 2007 Mar 20]. Available at: http://brainmaps. Conclusion org; accessed Mar 20, 2007. 11. Kim S, Brinkley J, Rosse C. Profile of on-line anatomy informa- We have proposed a model based on groups of cells or cell tion resources: Design and instructional implications. Clinical parts, which serves to represent neuronal connections be- Anatomy. 2003;16(1):55–71. tween brain structures in more detail than it has been thus 12. Rydmark M, Kling-Petersen T, Pascher R, Philip F. 3D visual- far possible. The model is capable of drawing valid infer- ization and stereographic techniques for medical research and ences on pathways in a nervous system. In combination with education. Studies in health technology and informatics. 2001; an ontology of functions, the group-oriented model of 81:434–9. functional neuroanatomy can be the starting point for a

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