The Return of Phineas Gage: Clues About the

Brain from the Skull of a Famous Patient

Hanna Damaslo, Thomas Grabowski, Randall Frank,

Albert M. Galaburda, Antonio R. Damasio*

When the landmark patient Phineas Gage died in 1861, no autopsy was performed, buthis skull was later recovered. The brain lesion that caused the profound personalitychanges for which his case became famous has been presumed to have involved the leftfrontal region, but questions have been raised about the involvement of other regions andabout the exact placement of the lesion within the vast frontal territory. Measurements fromGage's skull and modern neuroimaging techniques were used to reconstitute the accidentand determine the probable location of the lesion. The damage involved both left and rightprefrontal cortices in a pattern that, as confirmed by Gage's modern counterparts, causesa defect in rational decision making and the processing of emotion.

On 13 September 1848, Phineas P. Gage,a 25-year-old construction foreman for theRutland and Burlington Railroad in NewEngland, became a victim of a bizarre acci-dent. In order to lay new rail tracks acrossVermont, it was necessary to level theuneven terrain by controlled blasting.Among other tasks, Gage was in charge ofthe detonations, which involved drillingholes in the stone, partially filling the holeswith explosive powder, covering the powderwith sand, and using a fuse and a tampingiron to trigger an explosion into the rock.On the fateful day, a momentary distractionlet Gage begin tamping directly over thepowder before his assistant had had a chanceto cover it with sand. The result was apowerful explosion away from the rock andtoward Gage. The fine-pointed, 3-cm-thick,109-cm-long tamping iron was hurled, rock-et-like, through his face, skull, brain, andthen into the sky. Gage was momentarilystunned but regained full consciousness im-mediately thereafter. He was able to talk andeven walk with the help of his men. Theiron landed many yards away (1).

Phineas Gage not only survived themomentous injury, in itself enough to earnhim a place in the annals of medicine, buthe survived as a different man, and thereinlies the greater significance of this case.Gage had been a responsible, intelligent,and socially well-adapted individual, a fa-vorite with peers and elders. He had madeprogress and showed promise. The signs of a

H. Damasio and A. R. Damasio are in the Departmentof Neurology, University of Iowa Hospitals & Clinics,Iowa City, IA 52242, and the Salk Institute for Biolog-ical Research, San Diego, CA 92186-5800, USA. T.Grabowski and R. Frank are in the Department ofNeurology, University of Iowa Hospitals & Clinics, IowaCity, IA 52242, USA. A. M. Galaburda is in the Depart-ment of Neurology, Harvard Medical School, BethIsrael Hospital, Boston, MA 02215, USA.*To whom correspondence should be addressed.

1102

profound change in personality were al-ready evident during the convalescence un-der the care of his physician, John Harlow.But as the months passed it became appar-ent that the transformation was not onlyradical but difficult to comprehend. In somerespects, Gage was fully recovered. He re-mained as able-bodied and appeared to beas intelligent as before the accident; he hadno impairment of movement or speech;new learning was intact, and neither mem-ory nor intelligence in the conventionalsense had been affected. On the otherhand, he had become irreverent and capri-cious. His respect for the social conventionsby which he once abided had vanished. Hisabundant profanity offended those aroundhim. Perhaps most troubling, he had takenleave of his sense of responsibility. He couldnot be trusted to honor his commitments.His employers had deemed him "the mostefficient and capable" man in their "em-ploy" but now had to dismiss him. In thewords of his physician, "the equilibrium orbalance, so to speak, between his intellec-tual faculty and animal propensities" hadbeen destroyed. In the words of his friendsand acquaintances, "Gage was no longerGage" (1). Gage began a new life of wan-dering that ended a dozen years later, inSan Francisco, under the custody of hisfamily. Gage never returned to a fully in-dependent existence, never again held a jobcomparable to the one he once had. Hisaccident had made headlines but his deathwent unnoticed. No autopsy was obtained.

Twenty years after the accident, JohnHarlow, unaided by the tools of experimen-tal neuropsychology available today, per-ceptively correlated Gage's cognitive andbehavioral changes with a presumed area offocal damage in the frontal region (1).Other cases of neurological damage werethen revealing the brain's foundation for

SCIENCE * VOL. 264 * 20 MAY 1994

language, motor function, and perception,and now Gage's case indicated somethingeven more surprising: Perhaps there werestructures in the human brain dedicated tothe planning and execution of personallyand socially suitable behavior, to the aspectof reasoning known as rationality.

Given the power of this insight, Har-low's observation should have made thescientific impact that the comparable sug-gestions based on the patients of Broca andWernicke made (2). The suggestions, al-though surrounded by controversy, becamethe foundation for the understanding of theneural basis of language and were pursuedactively, while Harlow's report on Gage didnot inspire a search for the neural basis ofreasoning, decision-making, or social be-havior. One factor likely to have contrib-uted to the indifferent reception accordedHarlow's work was that the intellectualatmosphere of the time made it somewhat

A

Fig. 1. Photographs of (A) several views of theskull of Phineas Gage and (B) the skull x-ray.

on

Apr

il 14

, 201

4w

ww

.sci

ence

mag

.org

Dow

nloa

ded

from

o

n A

pril

14, 2

014

ww

w.s

cien

cem

ag.o

rgD

ownl

oade

d fr

om

on

Apr

il 14

, 201

4w

ww

.sci

ence

mag

.org

Dow

nloa

ded

from

o

n A

pril

14, 2

014

ww

w.s

cien

cem

ag.o

rgD

ownl

oade

d fr

om

more acceptable that there was a neuralbasis for processes such as movement oreven language rather than for moral reason-ing and social behavior (3). But the prin-cipal explanation must rest with the sub-stance of Harlow's report. Broca and Wer-nicke had autopsy results, Harlow did not.Unsupported by anatomical evidence, Har-low's observation was the more easily dis-missed. Because the exact position of thelesion was not known, some critics couldclaim that the damage actually involvedBroca's so-called language "center," andperhaps would also have involved the near-by "motor centers." And because the pa-tient showed neither paralysis nor aphasia,some critics reached the conclusion thatthere were no specialized regions at all (4).The British physiologist David Ferrier was arare dissenting voice. He thoughtfully ven-tured, in 1878, that the lesion spared bothmotor and language centers, that it haddamaged the left prefrontal cortex, and thatsuch damage probably explained Gage's be-havioral defects, which he aptly describedas a "mental degradation" (5).

Harlow only learned of Gage's deathabout 5 years after its occurrence. He pro-ceeded to ask Gage's family to have thebody exhumed so that the skull could berecovered and kept as a medical record.The strange request was granted, and Phin-

Fig. 2. View of the entry-level areawith the a priori most likely firsttrajectory. (A) Skull with this firstvector and the level (red) at whichentry points were marked. (B) Viewof a segment of section 1. On theleft is the mandibular ramus, andon the right is the array of entrypoints. (C) Enlargement of the ar-ray of entry points. One additionalpoint was added (L20) to ensurethat every viable entry point wassurrounded by nonviable points.Nonviable vectors are shown in redand viable vectors with labels iden-tifying their exit points are shown ingreen. Abbreviations: A, anterior;L, lateral; P, posterior; AM, anteromesial; AL, anterolateral; F

eas Gage was once again the protagonist ofa grim event. As a result, the skull and thetamping iron, alongside which Gage hadbeen buried, have been part of the WarrenAnatomical Medical Museum at HarvardUniversity.

As new cases of frontal damage weredescribed in this century, some ofwhich didresemble that of Gage, and as the enigmasof frontal lobe function continued to resistelucidation, Gage gradually acquired land-mark status. Our own interest in the casegrew out of the idea that Gage exemplifieda particular type of cognitive and behavior-al defect caused by damage to ventral andmedial sectors of prefrontal cortex, ratherthan to the left dorsolateral sector as im-plicit in the traditional view. It then oc-curred to us that some of the image process-ing techniques now used to investigateGage's counterparts could be used to testthis idea by going back in time, reconsti-tuting the accident, and determining theprobable placement of his lesion. The fol-lowing is the result of our neuroanthropo-logical effort.We began by having one of us (A.M.G.)

photograph Gage's skull inside and out andobtain a skull x-ray (Fig. 1) as well as a set ofprecise measurements (6) relative to bonelandmarks. Using these measurements, weproceeded to deform linearly the three-di-

PL, posterolateral; C, central.

Fig. 3. (A) View from above the A 11

deformed skull with the exit hole 12 * 10

and the anterior bone flap traced inblack. The blue circle represents _ _ 1 -

the first vector tested, and the graysurface represents the area where

exit points were tested. (B) Sche-matic enlargement of the exit hole 5

and of the area tested for exit 3

points. The letter C marks the first

tested vector (blue). The numbers1 through 15 mark the other exit

points tested. Red indicates nonvi-

able vectors, green indicates via-ble vectors, and the label identifies the entry point. Note that the a priori best fit C was not viable.

SCIENCE * VOL. 264 * 20 MAY 1994

mensional reconstruction of a standard hu-man skull (7) so that its dimensions matchedthose of Phineas Gage's skull. We also con-structed Talairach's stereotactic space forboth this skull and Phineas Gage's real skull(8). On the basis of the skull photographs,the dimensions of the entry and exit holeswere scaled and mapped into the deformedstandard skull. Based on measurements ofthe iron rod and on the recorded descrip-tions of the accident, we determined therange of likely trajectories of the rod. Final-ly, we simulated those trajectories in three-dimensional space using Brainvox (9). Wemodeled the rod's trajectory as a straight lineconnecting the center of the entry hole atorbital level to the center of the exit hole.This line was then carried downward to thelevel of the mandibular ramus. The skullanatomy allowed us to consider entry pointswithin a 1.5-cm radius of this point (20points in all) (Fig. 2).

Possible exit points were determined asfollows: We decided to constrain the exitpoint to be at least 1.5 cm (half the diam-eter of the rod) from the lateral and poste-rior margins of the area of bone loss (Fig. 3)because there were no disruptions of theouter table of the calvarium in these direc-tions (Fig. 1, lower right panel). However,we accepted that the rod might have passedup to 1.5 cm anterior to the area ofbone lossbecause inspection of the bone in this regionrevealed that it must have been separatedcompletely from the rest of the calvarium(Fig. 1). Furthermore, the wound was de-scribed as an inverted funnel (1). We tested16 points within the rectangular-shaped exitarea that we constructed (Fig. 3).

The trajectory connecting each of theentry and exit points was tested at multipleanatomical levels. The three-dimensionalskull was resampled in planes perpendicularto the best a priori trajectory (C in Figs. 2and 3). We were helped by several impor-tant anatomical constraints. We knew thatthe left mandible was intact; that the zygo-matic arch was mostly intact but had achipped area, at its medial and superioredge, that suggested the rod had grazed it;and that the last superior molar socket wasintact although the tooth was missing. Ac-ceptable trajectories were those which, ateach level, did not violate the followingrules: The vectors representing the trajecto-ries could not be closer than 1.5 cm from themid-thickness of the zygomatic arch, 1 cmfrom the last superior molar, and 0.5 cmfrom the coronoid process of the mandible(10). Only seven trajectories satisfied theseconditions (Fig. 4). Two of those seveninvariably hit the anterior horn of the lateralventricle and were therefore rejected as an-atomically improbable because they wouldnot have been compatible with survival (theresulting massive infection would not have

1103

c 4ntod)r 1M -15 .. is

Ah -10 A 0 1110a- a

m 5 1 LW-- ~Jul

a 0Aa a1

jpi0 P1,10a

aq a &SO. p.s PL 15p.wtoribr1

M~

Fig. 4. (A) Front and lateral skull views with theprojection of the five final vectors (V). The twored lines show the position of the two sectionsseen in (B). (B) Skull sections 2 and 3: examplesof two bottleneck levels at which the viability ofvectors was checked. Next to each section is anenlargement of the critical area. Abbreviations:T, missing tooth; M, intact mandible; Z, intactzygoma with a chipped area (light blue).

been controllable in the preantibiotic era).When checked in our collection of normalbrains, one of the remaining five trajectoriesbehaved better than any other relative to thelower constraints and was thus chosen as themost likely trajectory. The final step was tomodel the five acceptable trajectories of theiron rod in a three-dimensional reconstruc-tion of a human brain that closely fit PhineasGage's assumed brain dimensions (1 1). Ta-lairach's stereotactic warpings were used forthis final step.

The modeling yielded the results shown inFig. 5. In the left hemisphere, the lesioninvolved the anterior half of the orbital fron-tal cortex (Brodmann's cytoarchitectonicfields 11 and 12), the polar and anteriormesial frontal cortices (fields 8 to 10 and 32),and the anterior-most sector of the anteriorcingulate gyrus (field 24). However, the le-sion did not involve the mesial aspect of field6 Ithe supplementary motor area (SMA) I.

Fig. 5. Normal brainfitted with the five pos-sible rods. The best rodis highlighted in solidwhite [except for (B),where it is shown inred]. The areas sparedby the iron are high-lighted in color: Broca,yellow; motor, red; soma-tosensory, green; Wer-nicke, blue. (A) Lateralview of the brain. Num-bered black lines corre-spond to levels of thebrain section shown in(C). (D and E) Medicalview of left and righthemispheres, respec-tively, with the rodshown in white.

D

A

8.

614,21

The frontal operculum, which contains Bro-ca's area and includes fields 44, 45, and 47,was also spared, both cortically and in theunderlying white matter. In the right hemi-sphere, the lesion involved part of the ante-

B

7.53

E

rior and mesial orbital region (field 12), themesial and polar frontal cortices (fields 8 to 10and 32), and the anterior segment of theanterior cingulate gyrus (field 24). The SMAwas spared. The white matter core of thefrontal lobes was more extensively damaged inthe left hemisphere than in the right. Therewas no damage outside of the frontal lobes.

Even allowing for error and taking intoconsideration that additional white matterdamage likely occurred in the surround ofthe iron's trajectory, we can conclude thatthe lesion did not involve Broca's area or themotor cortices and that it favored the ven-tromedial region of both frontal lobes whilesparing the dorsolateral. Thus, Ferrier wascorrect, and Gage fits a neuroanatomicalpattern that we have identified to date in 12patients within a group of 28 individualswith frontal damage (12). Their ability tomake rational decisions in personal and so-cial matters is invariably compromised andso is their processing of emotion. On thecontrary, their ability to tackle the logic ofan abstract problem, to perform calcula-tions, and to call up appropriate knowledgeand attend to it remains intact. The estab-lishment of such a pattern has led to thehypothesis that emotion and its underlyingneural machinery participate in decisionmaking within the social domain and hasraised the possibility that the participationdepends on the ventromedial frontal region(13). This region is reciprocally connectedwith subcortical nuclei that control basicbiological regulation, emotional processing,and social cognition and behavior, for in-stance, in amygdala and hypothalamus (14).Moreover, this region shows a high concen-

SCIENCE * VOL. 264 * 20 MAY 1994

y1001U;-

1104

tration of serotonin S2 receptors in monkeyswhose behavior is socially adapted as well asa low concentration in aggressive, sociallyuncooperative animals (15). In contrast,structures in the dorsolateral region are in-volved in other domains of cognition con-cerning extrapersonal space, objects, lan-guage, and arithmetic (16). These structuresare largely intact in Gage-like patients, thusaccounting for the patients' normal perfor-mance in traditional neuropsychologic teststhat are aimed at such domains.

The assignment of frontal regions todifferent cognitive domains is compatiblewith the idea that frontal neurons in any ofthose regions may be involved with atten-tion, working memory, and the categoriza-tion of contingent relationships regardlessof the domain (17). This assignment alsoagrees with the idea that in non-brain-damaged individuals the separate frontalregions are interconnected and act cooper-atively to support reasoning and decisionmaking. The mysteries of frontal lobe func-tion are slowly being solved, and it is onlyfair to establish, on a more substantialfooting, the roles that Gage and Harlowplayed in the solution.

REFERENCES AND NOTES

1. J. M. Harlow, Pub. Mass. Med. Soc. 2,327 (1868).2. P. Broca, Bull. Soc. Anthropol. 6, 337 (1865); C.

Wernicke, Der aphasische Symptomencomplex(Cohn und Weigert, Breslau, Poland, 1874). Aremarkable number of basic insights on the func-tional specialization of the human brain, frommotor function to sensory perception and to spo-ken and written language, came from the descrip-tion of such cases mostly during the second halfof the 19th century. The cases usually acted as aspringboard for further research, but on occasiontheir significance was overlooked, as in the caseof Gage. Another such example is the descriptionof color perception impairment (achromatopsia)caused by a ventral occipital lesion, by D. Verrey[Arch. Ophthalmol. (Paris) 8, 289 (1888)]. Hisastonishing finding was first denied and thenignored until the 1970s.

3. Reasoning and social behavior were deemedinextricable from ethics and religion and not ame-nable to biological explanation.

4. The reaction against claims for brain specializa-tion was in fact a reaction against phrenologicaldoctrines, the curious and often unacknowledgedinspiration for many of the early case reports. Theviews of E. Dupuy exemplify the attitude [Examende Quelques Points de la Physiologie du Cerveau(Delahaye, Paris, 1873); M. MacMillan, Brain Cog-nit. 5, 67 (1986)].

5. D. Ferrier, Br. Med. J. 1, 399 (1878).6. The first measurements were those necessary to

construct Gage's Talairach stereotactic spaceand deform a three-dimensional, computerizedtomography skull: the maximum length of theskull, the maximum height of the skull above theinion-glabella line, the distance from this line tothe floor of the middle fossa, the maximum widthof the skull, and the position of the section contourof Gage's skull relative to the inion-glabella line.The second measurements were those necessaryto construct the entry and exit areas: on the topexternal view, the measure of edges of the trian-gular exit hole; on the internal view the distancesfrom its three corners to the mid-sagittal line andto the nasion; the distance from the borders of thehole to the fracture lines seen anteriorly and

posteriorly to this hole; and the dimensions of theentry hole at the level of the orbit.

7. Thin-cut standard computerized tomography im-age of a cadaver head obtained at North CarolinaMemorial Hospital.

8. We introduced the following changes to the meth-od described by P. Fox, J. Perlmutter, and M.Raichle [J. Comput. Assist. Tomogr. 9, 141(1985)]. We calculated the mean distance fromthe anterior commissure (AC) to the posteriorcommissure (PC) in a group of 27 normal brainsand used that distance for Gage (26.0 mm). Wealso did not consider the AC-frontal pole and thePC-occipital pole distances as equal becauseour group of normals had a mean difference of 5mm between the two measures, and Talairachhimself did not give these two measurements asequal [J. Talairach and G. Szikla, Atlas dAnat-omie Stereotaxique du Telencephale (Masson,Paris, 1967); J. Talairach and P. Tournoux, Co-Planar Stereotaxic Atlas of the Human Brain(Thieme, New York, 1988)]. We introduced ananterior shift of 3% to the center of the AC-PCline and used that point as the center of theAC-PC segment. This shift meant that the ante-rior sector of Talairach's space was 47% of thetotal length and that the posterior was 53%. Wehad no means of calculating the difference be-tween the right and left width of Gage's brain;therefore, we assumed them to be equal.

9. H. Damasio and R. Frank, Arch. Neurol. 49, 137(1992).

10. There were two reasons to allow the vector thisclose to the mandible: (i) The zygomatic arch andthe coronoid process were never more than 2 cmapart; (ii) we assumed that, in reality, this distancemight have been larger if the mouth were open orif the mandible, a movable structure, had beenpushed by the impact of the iron rod.

11. The final dimensions of Phineas Gage's Talairachspace were as follows: total length, 171.6 mm;total height, 111.1 mm; and total width, 126.5 mm.Comparing these dimensions to a group of 27normal subjects, we found that in seven cases atleast two of the dimensions were close to those of

Phineas Gage [mean length, 169.9 mm (SD, 4.1);mean height, 113.6 (SD, 2.3); mean width, 125(SD, 3.9). The seven brains were fitted with thepossible trajectories to determine which brainareas were involved. There were no significantdifferences in the areas of damage. The modelingwe present here was performed on subject1 600LL (length, 169 mm; height, 1 15.2 mm; width,125.6 mm).

12. Data from the Lesion Registry of the University ofIowa's Division of Cognitive Neuroscience as of1993.

13. P. Eslinger and A. R. Damasio, Neurology 35,1731 (1985); J. L. Saver and A. R. Damasio,Neuropsychologia 29, 1241 (1991); A. R. Dama-sio, D. Tranel, H. Damasio, in Frontal Lobe Func-tion and Dysfunction, H. S. Levin, H. M. Eisen-berg, A. L. Benton, Eds. (Oxford Univ. Press, NewYork, 1991), pp. 217-229; S. Dehaene and J. P.Changeux, Cereb. Cortex 1, 62 (1991).

14. P. S. Goldman-Rakic, in Handbook of Physiology;The Nervous System, F. Plum, Ed. (AmericanPhysiological Society, Bethesda, MD, 1987), vol.5, pp. 373-401; D. N. Pandya and E. H. Yeterian,in The Prefrontal Cortex: Its Structure, Functionand Pathology, H. B. M. Uylings, Ed. (Elsevier,Amsterdam, 1990); H. Barbas and D. N. Pandya,J. Comp. Neurol. 286, 253 (1989).

15. M. J. Raleigh and G. L. Brammer, Soc. Neurosci.Abstr. 19, 592 (1993).

16. M. Petrides and B. Milner, Neuropsychologia 20,249 (1982); J. M. Fuster, The Prefrontal Cortex(Raven, New York, ed. 2, 1989); M. I. Posner andS. E. Petersen, Annu. Rev. Neurosci. 13, 25(1 990) .

17. P. S. Goldman-Rakic, Sci. Am. 267, 1 10 (Septem-ber 1992); A. Bechara, A. R. Damasio, H. Dama-sio, S. Anderson, Cognition 50, 7 (1994); A. R.Damasio, Descartes' Error: Emotion, Reason andthe Human Brain (Putnam, New York, in press).

18. We thank A. Paul of the Warren Anatomical Mu-seum for giving us access to Gage's skull. Sup-ported by National Institute of Neurological Dis-eases and Stroke grant P01 NS19632 and by theMathers Foundation.

92RESEARCH ARTICLE::::....

Highly Conjugated, AcetylenylBridged Porphyrins: New Models forLight-Harvesting Antenna Systems

Victor S.-Y. Lin, Stephen G. DiMagno, Michael J. Therien*

A new class of porphyrin-based chromophore systems has been prepared from ethyne-elaborated porphyrin synthons through the use of metal-mediated cross-coupling meth-

odologies. These systems feature porphyrin chromophores wired together through singleethynyl linkages. This type of topological connectivity affords exceptional electronic inter-actions between the chromophores which are manifest in their room temperature photo-physics, optical spectroscopy, and electrochemistry; these spectroscopic signatures in-

dicate that these species model many of the essential characteristics of biological light-harvesting antenna systems.

The optical, electronic, and photophysicalproperties of porphyrins have made thesemolecules desirable targets for incorpo-ration into supramolecular systems andpolymers due to their central importance in

SCIENCE * VOL. 264 * 20 MAY 1994

the developing biomimetic chemistry ofmultichromophoric assemblies in biology aswell as for potential application in sensing(1), opto-electronic (2), magnetic (3), ar-tificial photosynthetic (4, 5), catalytic (6),

1105

... *awe.,.§k