The mapping of human brain connectivity through the use of modern neuroimaging methods has enjoyed considerable interest, examination, and application in recent years 
. Through the use of diffusion weighted (DWI) and magnetic resonance imaging (MRI), it is possible to systematically assess white matter (WM) fiber pathways between brain regions to measure fiber bundle properties, their influence on behavior and cognition, as well as the results of severe brain damage. The potential for using combined DWI/MRI methods to understand network-level alterations resulting from neurological insult is among their major research and clinical advantages.
In this paper, we investigate the detailed connectomics of a noted example of severe traumatic brain injury (TBI) which has proved important to and controversial in the history of neuroscience. Few cases in the history of the medical sciences have been so important, interpreted, and misconstrued, as the case of Phineas P. Gage 
, in whom a “tamping iron” was accidentally shot through his skull and brain, resulting in profound behavioral changes, and which contributed to his death 151 years ago. On September 13th, 1848, the 25-year old Phineas P. Gage was employed as a railroad construction supervisor near Cavendish, Vermont to blast and remove rock in preparation for the laying of the Rutland and Burlington Railroad. Having drilled a pilot hole into the rock and filling it partially with gunpowder, he instructed an assistant to pour sand into the hole atop the powder. Averting his attention for a moment to speak with his men, he apparently assumed the sand had been added. He then commenced dropping the end of a 110 cm long, 3.2 cm diameter iron rod into the hole in order to “tamp” down its contents. The 13 lb. iron struck the interior wall of the hole causing a spark to ignite the powder which, in turn, launched the pointed iron rod upwards, through the left cheek of Mr. Gage just under the zygomatic arch, passing behind his left eyeball, piercing his cranial vault under the left basal forebrain, passing through his brain, and then exiting the top and front of his skull near the sagittal suture. A large amount of brain tissue was expelled from the opening and the rod was found later “smeared with blood and brains”, washed in a stream, and, eventually, returned to him. After receiving treatment and care from Dr. John Martyn Harlow over subsequent weeks, Mr. Gage was able to recover sufficiently from his physical injuries and return to his family in nearby New Hampshire. However, reports of profound personality changes indicate that he was unable to return to his previous job and caused co-workers to comment that he was “no longer Gage.” Following several years of taking manual labor jobs and travelling throughout New England and eventually to Valparaiso, Chile, always in the company of “his iron”, he was reunited with his family in San Francisco whereupon Mr. Gage died on May 21, 1860, nearly 12 years after his injury – presumably due to the onset of seizures evidently originating from damage resulting from the tamping rod incident. Several years later, Dr. Harlow, upon learning of Gage's death, asked Gage's sister's family to exhume his body to retrieve his skull and rod for presentation to the Massachusetts Historical Society and deposition with Harvard Medical School where, to this day, it remains on display in the Warren Anatomical Museum in the Francis A. Countway Library of Medicine at Harvard Medical School ().
Modeling the path of the tamping iron through the Gage skull and its effects on white matter structure.
The amount of damage to Mr. Gage's left frontal cortical grey matter (GM) with secondary damage to surrounding GM has been considered by several authors with reference to Gage's reported change in temperament, character, etc 
(). With the aid of medical imaging technology, two previous published articles have sought to illustrate the impact of the rod on Mr. Gage's skull and brain. Most famously, Damasio et al.
illustrated that the putative extent of damage to the left frontal cortex would be commensurate with the disinhibition, failures to plan, memory deficiencies, and other symptoms noted in patients having frontal lobe injury. Ratiu et al.
sought to illustrate the trajectory of the tamping iron, characterize the pattern of skull damage, and explain potential brain damage using a single, example subject. However, while many authors have focused on the gross damage done by the iron to Gage's frontal cortical GM, little consideration has been given to the degree of damage to and destruction of major connections between discretely affected regions and the rest of his brain.
Estimates of the Damage to Gage's Brain.
WM fasciculi link activity between cortical areas of the brain 
, become systematically myelinated through brain maturation 
, govern fundamental cognitive systems 
, and may be disrupted in neurological 
and psychiatric disease 
. Penetrative TBI in cases of wartime 
, industrial 
, gunshot 
, or domestic 
injury often result in significant damage to brain connectivity, loss of function, and often death. Yet, in some instances, recovery from objects penetrating WM 
have been reported with minimal sequelae 
. Neuroimaging studies of WM tracts in TBI have revealed not only significant acute damage to fiber pathways but also that measures of fiber integrity can show partial fiber recovery over time 
, presumably due to cortical plasticity 
in non-penetrative cases.
Given recent interest in the atlasing of the human WM connectome (e.g. http://www.humanconnectomeproject.org
), a detailed consideration of the putative damage to Mr. Gage's connectomics and implications for changes in behavior is provocative and compelling. Nerve damage is superficially evident through reports of eventual loss of sight in Gage's left eye, left eyelid ptosis 
, and recognition of potential WM damage by other investigators 
. Further examination of the extent of Gage's WM damage and of its effects on network topology and regional connectedness can offer additional context into putative behavioral changes. Due to the absence of original brain tissue and to the lack of a recorded autopsy from this case, one can only estimate the extent of damage from bony structures and can never be confident concerning which precise brain tissues were impacted. However, brain tissue in situ
from a representative population can be considered and it can be assumed that Mr. Gage's anatomy would have been similar. In this examination, we obtained the original high-resolution CT data of the Gage skull used by Ratiu et al.
, and computationally estimated the best-fit rod trajectory through the skull. Via multimodal analysis of T1-weighted anatomical MRI and DWI in N
110 normal, right-handed males, aged 25–36, we quantify the extent of acute regional cortical loss and examine in detail the expected degree of damage to Mr. Gage's WM pathways.