Dynamic imaging in mild traumatic brain injury- Support for the theory of medial temporal vulnerabil

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Dynamic Imaging in Mild Traumatic Brain Injury: Support for the Theory of Medial Temporal Vulnerability Eric M. Umile, PsyD, M. Elizabeth Sandel, MD, Abass Alavi, MD, Charles M. Terry, MD, Rosette C. Plotkin, PhD ABSTRACT. Umile EM, Sandel ME, Alavi A, Terry CM, Plotkin RC. Dynamic imaging in mild traumatic brain injury: support for the theory of medial temporal vulnerability. Arch Phys Med Rehabil 2002;83:1506-13.

Objective: To determine whether patients with mild traumatic brain injury (TBI) and persistent postconcussive symptoms have evidence of temporal lobe injury on dynamic imaging.

Design: Case series.

Setting: An academic medical center.

Participants: Twenty patients with a clinical diagnosis of mild TBI and persistent postconcussive symptoms were referred for neuropsychologic evaluation and dynamic imaging.

Fifteen (75%) had normal magnetic resonance imaging (MRI) and/or computed tomography (CT) scans at the time of injury.

Interventions: Neuropsychologic testing, positron-emission tomography (PET), and single-photon emission-computed tomography (SPECT).

Main Outcome Measures: Temporal lobe findings on static imaging (MRI, CT) and dynamic imaging (PET, SPECT); neuropsychologic test findings on measures of verbal and visual memory.

Results: Testing documented neurobehavioral deficits in 19 patients (95%). Dynamic imaging documented abnormal findings in 18 patients (90%). Fifteen patients (75%) had temporal lobe abnormalities on PET and SPECT (primarily in medial temporal regions); abnormal findings were bilateral in 10 patients (50%) and unilateral in 5 (25%). Six patients (30%) had frontal abnormalities, and 8 (40%) had nonfrontotemporal abnormalities. Correlations between neuropsychologic testing and dynamic imaging could be established but not consistently across the whole group.

Conclusions: Patients with mild TBI and persistent postconcussive symptoms have a high incidence of temporal lobe injury (presumably involving the hippocampus and related structures), which may explain the frequent finding of memory disorders in this population. The abnormal temporal lobe findings on PET and SPECT in humans may be analogous to the neuropathologic evidence of medial temporal injury provided by animal studies after mild TBI.

From the Departments of Rehabilitation Medicine (Umile, Plotkin) and of Radiology (Alavi), University of Pennsylvania Medical Center, Philadelphia, PA; Kaiser Permanente Medical Center, Kaiser Foundation Rehabilitation Center, Vallejo, CA (Sandel); and Brain Injury Unit, St. Lawrence Rehabilitation Center, Lawrenceville, NJ (Terry).

Supported in part by the National Institutes of Health (grant no. P50-NS08803).

Portions of this article were presented at the American Academy of Physical Medicine and Rehabilitation’s Annual Assembly, November, 15, 1997, Atlanta, GA. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated.

Reprint requests to M. Elizabeth Sandel, MD, Kaiser Permanente Medical Center, Kaiser Foundation Rehabilitation Center, 975 Sereno Dr, Vallejo, CA 94589-2485, e-mail: elizabeth.sandel@kp.org.

0003-9993/02/8311-7010$35.00/0 doi:10.1053/apmr.2002.35092

Arch Phys Med Rehabil Vol 83, November 2002

Key Words: Brain injuries; Postconcussion syndrome; Rehabilitation; Tomography, positron-emission; Tomography, emission-computed, single-photon. Š 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation ILD TRAUMATIC BRAIN INJURY (TBI) represents a significant health problem in the United States and has an M annual incidence of 180 in 100,000. The incidence of mild TBI victims who report persistent symptoms is approximately 27 in 100,000 (or an estimated 15% of all persons who sustain these injuries).1 Mild concussion (with or without loss of consciousness [LOC]) was once regarded as a reversible condition. This idea was challenged in the mid-1980s by studies suggesting that the morbidity associated with mild TBI was significantly underestimated.2 It is now recognized that LOC is not a necessary prerequisite for developing the sequelae of mild TBI.3 This idea was acknowledged by experts in the fields of neuropsychology and rehabilitation medicine who developed a working definition of mild TBI that includes persons who have impairments of consciousness without LOC.4 Most persons who sustain a mild TBI will completely recover within 3 months.5-10 Nevertheless, a subset of mild brain-injured persons will experience continuing symptoms and cognitive deficits associated with postconcussion syndrome. Persistent cognitive deficits have been noted in patients at 3 months,11,12 6 months,13 1 year,14,15 and beyond 1 year.16,17 According to 1 estimate,1 about 15% of mild TBI patients will experience persistent, disabling symptoms beyond 6 months.

Memory and learning disturbances are the most frequently reported cognitive symptoms after TBI.18,19 Because a number of factors can produce memory deficits in TBI patients, a broad-based, systematic assessment of brain functions across several neurocognitive domains is often necessary to make an accurate differential diagnosis. If attentional problems, executive function deficits, poor motivation, and/or malingering can be ruled out, the memory disturbances may be explained by damage or disruption of function in the medial temporal lobes.

The medial temporal lobes (and related structures in the diencephalon) play a crucial role in normal memory functioning.20 Collectively, these structures support the ability to consciously recall facts and events (ie, declarative memory) but are unnecessary for nonconscious forms of memory that are expressed through performance (eg, procedural skills, habits).21 One conceptual model of memory proposes that medial temporal lobe structures permit storage and retrieval of memories until the process of consolidation is completed, possibly by specifying the storage site in the neocortex, or by permitting consolidation through the linkage of different neocortical storage sites that together represent a whole memory.22,23 The hippocampus, a key structure in the medial temporal lobe, plays an important role in memory and learning. It is located within the hippocampal formation, a collection of cytoarchitectonically distinct subdivisions that also includes the

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dentate gyrus, subicular complex, and entorhinal cortex.24 The hippocampus is especially vulnerable to mechanically induced head injury and to other types of central nervous system insults such as ischemia, hypoxia, and seizures.25 Some research has shown that the extent of damage to the hippocampal region of the hippocampal formation is correlated with severity of memory impairment.26 Animal studies have documented neuropathologic evidence of structural damage in the medial temporal lobes after mild or moderate TBI. Kotapka et al27 delivered mild acceleration-type experimental head injuries to nonhuman primates and found hippocampal lesions in virtually all animals injured in the lateral plane, 75% of animals injured in the oblique plane, and 48% of animals injured in the sagittal plane. Hicks et al25 examined the effects of experimentally induced moderate TBI on memory function, regional neuronal loss in the hippocampi, and disruption of the blood-brain barrier in rats. Significant memory deficits were noted in the rats within 48 hours of injury. A significant correlation was found between memory dysfunction and neuronal loss in the hilar region of the dentate gyrus and pyramidal cell layer CA3 in the hippocampus. The rats also had extensive disruption of the blood-brain barrier in the ipsilateral cortex and hippocampus, even though hemorrhage was either limited or absent in those areas. In a third study, Smith et al28 found that bilateral dentate hilar neuron loss was a consistent neuropathologic feature 2 weeks after mild TBI and was uniformly associated with memory dysfunction.

Memory dysfunction in humans may be similarly associated with selective loss of bilateral hippocampal dentate hilar neurons after mild TBI. However, neuropathologic studies of humans after mild TBI are scarce (because of the extremely low mortality rate associated with this type of injury). Consequently, structural damage in humans after mild TBI must be evaluated using different approaches. Computed tomography (CT) can detect small petechial hemorrhages consistent with diffuse axonal injury (DAI) in patients with mild TBI.29 Magnetic resonance imaging (MRI) has been found to be more sensitive to traumatic lesions than CT.30 It is generally the case, however, that patients with mild injuries have normal static images, even during the acute postinjury period.

Dynamic imaging modalities such as single-photon emission-computed tomography (SPECT) and positron-emission tomography (PET) allow a visualization of brain function or physiology. They are comparable with regard to the results generated and can be used to measure regional cerebral blood flow, cerebral blood volume, and activity at neurotransmitter sites.31 SPECT is more sensitive than CT in detecting lesions, especially in patients with milder injuries.32 It is now well established that PET is somewhat superior to SPECT in terms of spatial resolution and permits a better visualization of subtle abnormalities. On the other hand, SPECT is generally more affordable (primarily because a cyclotron is not required). It is widely available in most institutions around the world and can be routinely used for evaluating brain injury without significant limitations.33 Dynamic imaging has been shown to have prognostic value in evaluating mild TBI patients. For example, Jacobs et al34 found that a normal initial SPECT scan reliably predicted a good clinical outcome at 3 months. They found that 95% of patients with persistent postconcussive symptoms and/or clinical signs at 3 months postinjury also had abnormal SPECT scans at 3 months.

Our study focuses on a case series of patients with a clinical diagnosis of mild TBI who subsequently developed persistent postconcussive symptoms for which they sought medical treat-

ment. We attempted to clarify the nature of the anatomic and physiologic abnormalities produced by each patient’s injury using PET or SPECT and to correlate the dynamic imaging findings with their cognitive profiles on neuropsychologic testing. In particular, we sought to determine the number of patients for whom there was converging evidence of temporal lobe defects on dynamic imaging and memory deficits on neuropsychologic testing. We interpreted such correspondences as evidence supporting the theory of medial temporal vulnerability in mild TBI. METHODS Participants Subjects were identified retrospectively from among the population of patients with head trauma who presented to the outpatient rehabilitation center of a large urban academic medical center over a 2-year period. All subjects had presented for evaluation of persistent cognitive and somatic complaints after a mild TBI. Each subject’s clinical record was thoroughly reviewed to establish eligibility for inclusion in the sample.

Subjects were included if they met the definition of mild TBI proposed by the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine.4 That is, they reportedly had any period of LOC or alteration in mental status not greater than 30 minutes, any memory loss for events immediately before or after their injury, and/or any period of posttraumatic amnesia not greater than 24 hours.

None of the subjects had an initial Glasgow Coma Scale score less than 13. Only those patients who subsequently underwent comprehensive neuropsychologic testing and dynamic imaging (PET or SPECT) were included in the final sample. Patients with a history of more than 1 TBI, premorbid psychiatric problems, or neurologic diagnosis other than brain injury were excluded.

Demographic and clinical data on the final sample are presented in table 1. Twenty patients were included (11 men, 9 Table 1: Patient Demographic and Injury Information

Subject

Age at Injury (y)

Sex

Hand Dominance

Education (y)

Injury

LOC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

55 23 32 25 30 32 41 59 52 26 55 39 28 19 35 39 23 39 45 47

M F F M M F F M M F F M M F M F M M F M

R R R R R R R R R R R R R R R R R R R R

10 13 16 13 15 12 12 12 12 16 12 16 14 16 12 19 16 19 19 20

Fall MVC MVC Hit by plank Fall MVC MVC Assault Fall Hit by car Hit by box MVC MVC MVC MVC MVC MVC MVC MVC MVC

⬍30min ⬍60s None ⬍30min None ⬍30min ⬍60s None ⬍30min ⬍60s None ⬍60s ⬍60s ⬍30min ⬍60s None ⬍30min ⬍30min None ⬍60s

Abbreviations: M, male; R, right; F, female; MVC, motor vehicle crash.

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women). Their age at time of injury ranged from 19 to 59 years (mean, 37.2y). All patients were right-handed. Their mean educational level was 14.7 years (range, 10 –20y). The interval between date of injury and date of referral was quite variable and ranged from 2 weeks to 7 years and 9 months. Motor vehicle crash was the cause of injury in 13 patients, 3 patients suffered falls, 2 were struck by falling objects, 1 was struck by a car, and 1 was assaulted.

History and Physical Examination Fourteen patients (70%) had sustained an LOC at the time of injury. In these cases, the period of unconsciousness lasted from several seconds to a few minutes. Six patients (30%) reported experiencing an alteration of mental status (eg, dazing) at the time of injury but without LOC. All patients reported a range of cognitive and somatic symptoms on initial presentation to the outpatient center. The most common cognitive problems (and percentage of subjects affected) were memory deficits (85%), concentration and information processing problems (60%), and word-finding difficulties (25%). The most common somatic symptoms were headache (90%), visual disturbance (75%), auditory disturbance (65%), sleep disturbance (60%), and impaired balance (55%).

A medical examination (including brief mental status and general neurologic examinations) revealed short-term memory impairment in 10 subjects (50%), impaired tandem gait in 9 (45%), and Romberg sign in 8 (40%). Psychologic assessment revealed evidence of depression in 13 subjects (65%), irritability in 13 (65%), emotional lability in 11 (55%), and anxiety in 8 (40%).

All patients had static imaging scans (MRI and/or CT); most scans were performed during the acute postinjury period or shortly thereafter. Twelve patients had MRI alone, 5 patients had CT alone, and 3 patients had both MRI and CT. Scans were characterized as either normal or abnormal based on the nature of the findings.

Dynamic Imaging All patients underwent either PET or SPECT: 13 had PET and 7 had SPECT. The choice of study was determined by insurance reimbursement parameters; whenever possible, a PET study was ordered because resolution is greater with PET than with SPECT. The mean interval from date of injury to date of dynamic imaging was 586 days (range, 42–2846d).

PET studies were performed after administration of 115mCi of 18F-fluorodeoxyglucose. Images were obtained 40 to 45 minutes after injection of the radiopharmaceutical, utilizing a Penn-PET 240H Scanner.a The SPECT studies were performed after administration of 20 to 25mCi of technetium 99m–labeled ethyl cysteinate dimer or hexamethyl propyleneamine oxime.

Images were acquired 45 to 60 minutes after injection by using a Picker Prism 3000 triple detector SPECT systema equipped with high resolution converging collimator.

PET and SPECT images were reconstructed in all 3 planes for the purpose of clinical interpretation. Images were qualitatively interpreted by experienced nuclear medicine physicians who did not have access to the findings of static imaging or neuropsychologic testing. (This approach to interpretation is consistent with accepted clinical practice in the field of nuclear medicine.) Images were visually inspected for abnormalities in both cortical and subcortical structures, and characterized as either normal or abnormal based on the nature of the findings.

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Neuropsychologic Testing All patients were evaluated by clinical neuropsychologists.

Eleven patients were tested by the same neuropsychologist at the outpatient center. The remaining 9 patients were tested by clinicians at other sites. Although the content of test batteries varied somewhat across patients (especially for patients tested at other sites), all test batteries emphasized the evaluation of cognitive abilities commonly impaired after mild TBI. The mean interval from date of injury to date of testing was 531 days (range 31–2899d).

Each patient’s neuropsychologic testing report was reviewed for evidence of neurobehavioral deficits. In this study, a deficit was defined as a test performance deemed by the evaluating neuropsychologist to be considerably below the patient’s estimated premorbid level of functioning (after correcting for variables, such as, age, sex, and education). A patient’s testing profile was characterized as either normal or abnormal depending on whether neurobehavioral deficits were present or not.

In particular, the performance of each patient on memory tests was analyzed for verbal and/or visual memory deficits. A brief description of the tests administered (and numbers of subjects who took each test) are presented below: Wechsler Memory Scale–Revised. The Wechsler Memory Scale–Revised35 test battery (18 patients) assesses verbal memory skills (story recall, word-paired associate learning, digit span repetitions) and visual memory skills (design reproduction, color-design paired associate learning, visuospatial tapping span repetitions). Most tasks incorporate immediate and delayed recall formats. (Note: One of our 20 patients took the original version of this test—the Wechsler Memory Scale— which is very similar to the revised version used for the other subjects.)

California Verbal Learning Test. The California Verbal Learning Test36 (14 patients) is a verbal learning task that assesses ability to learn and recall a shopping list. Acquisition and retention of the list is measured across 5 serial learning trials, after short- and long-delays, and under free- and cuedrecall conditions. Recognition memory is also measured.

Rey Complex Figure Test. The Rey Complex Figure Test37 (16 patients) assesses incidental visual recall for a complex geometric design. Subjects are initially told to copy the design (but without instructions to memorize it). Later, they are asked to reproduce the design from memory after postcopy intervals of 3 minutes and 30 minutes.

Rey Memorization of 15-Items Test. The Rey Memorization of 15-Items Test38 (2 patients) is a technique for evaluating patients’ cooperation and for assessing the validity of a memory complaint. Subjects must retain a visual array of 15 very basic symbols and numbers over a fixed time period and then reproduce them.

Portland Digit Recognition Test. The Portland Digit Recognition Test39 (1 patient) is a measure of recognition memory and working memory efficiency. On each trial, subjects hear a 5-digit number, and after intervals of varying length, must identify the number in a forced choice visual format. The task is made more difficult by making the subject perform a distractor activity (counting backward during the retention interval) on each trial.

Memory Assessment Scale. The Memory Assessment Scale40 (1 patient) assesses immediate and delayed recall for verbal and nonverbal material (word lists, stories, designs, face-name associations), as well as immediate recall for digit spans and visuospatial tapping spans. It also provides measures of recognition memory.

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Rey Auditory Verbal Learning Test. The Rey Auditory Verbal Learning Test41 (1 patient) evaluates the ability to learn a word list (acquisition), recall the list after short- and longdelays (retention), and recognize target words from the list in recognition formats. This test is similar to the California Verbal Learning Test, but does not incorporate measures of cued recall.

It should be noted that the memory assessment instruments used in this study were primarily measures of declarative memory, that is, the type of memory that is typically disrupted by damage to medial temporal lobe and diencephalic structures. As noted earlier, declarative memory is directly accessible to conscious recollection and deals with facts and information learned at particular times and places.21 It is the type of memory assessed by most current neuropsychologic tests.

Because all patients were referred for clinical reasons, neuropsychologic testing and dynamic imaging scans were not performed concurrently in most cases; the mean interval from date of testing to date of imaging was 110 days (range, 1–758d). It must be emphasized, however, that each patient’s postconcussive symptoms were characterized as chronic when they underwent these procedures. In other words, the 3-month period of spontaneous recovery that is commonly associated with most mild TBI cases had already elapsed.

Data Analysis Comparisons were made between diagnostic impressions (normal vs abnormal) of CT or MRI scans, PET or SPECT scans, and neuropsychologic test performance in patients with and without LOC. Descriptive statistics were tabulated for all relevant parameters. Because of limitations inherent to our retrospective design, no attempt was made to perform quantitative analyses of dynamic images and neuropsychologic test scores.

RESULTS Results of static imaging, dynamic imaging, and neuropsychologic test findings for patients with and without LOC are presented in table 2. Temporal lobe findings on dynamic imaging and memory deficits on neuropsychologic testing are presented in table 3.

Fifteen of 20 patients (75%) had normal static imaging scans and 5 patients (25%) had abnormal images. Abnormal brain MRI findings are summarized as follows: (1) mild to moderate bilateral cortical atrophy; (2) 2 discreet areas of old hemorrhagic blood products within the left frontal cortex and right parieto-occipital cortex, which were consistent with DAI; (3) patchy increased signal intensity in the pons; (4) left frontoparietal lesion consistent with contusion; and (5) multiple areas of increased signal intensity in the periventricular white matter, bilateral frontal regions, and right parietal subcortical white matter.

Dynamic Imaging Eighteen patients (90%) had cortical and/or subcortical abnormalities on PET or SPECT. Two patients (10%) had normal scans (table 2).

Fifteen patients (75%) had abnormalities in 1 or both temporal lobes. In terms of laterality, 10 patients (50%) had bilateral temporal abnormalities and 5 (25%) had unilateral temporal abnormalities. In the unilateral group, 4 patients (20%) had right temporal abnormalities and 1 patient (5%) had left temporal abnormalities (table 3). In terms of locality, the medial temporal regions were specifically affected in 11 patients (55%), the anterior temporal regions in 3 patients (15%), and the right superior temporal region in 1 patient (5%).

Table 2: Relationship of LOC to Abnormal Findings Abnormal Findings Subject

LOC

MRI/CT

PET/SPECT

Neuropsychologic Testing

1 2 4 6 7 9 10 12 13 14 15 17 18 20 3 5 8 11 16 19

⬍30min ⬍60s ⬍30min ⬍30min ⬍60s ⬍30min ⬍60s ⬍60s ⬍60s ⬍30min ⬍60s ⬍30min ⬍30min ⬍60s None None None None None None

Yes No No No No No Yes No No Yes No No No No No No No Yes No Yes

Yes Yes No Yes* Yes Yes Yes Yes Yes Yes* Yes Yes Yes Yes Yes Yes No Yes Yes Yes

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes

* Mild to moderate hypoperfusion in medial temporal lobes (possibly a normal variant).

Whereas the majority of patients in our case series (75%) had defects in the temporal lobes, only 6 patients (30%) had defects in the frontal lobes. Finally, 8 patients (40%) had diffuse or focal defects in locations other than the frontal or temporal lobes: of these 8 patients, 4 patients (20%) had parietal abnormalities, 3 (15%) had occipital abnormalities, and 5 (25%) had subcortical abnormalities in the left thalamus, left and/or right caudate nucleus, left putamen, and anterior cingulate.

Neuropsychologic Testing Nineteen of 20 patients (95%) had abnormal findings on neuropsychologic testing. In each case, the pattern of neurobehavioral deficits was consistent with a diagnosis of mild TBI. One patient (5%) had a normal testing profile.

With respect to performance on memory testing, 19 patients (95%) had verbal memory deficits and 14 patients (70%) had visual memory deficits (table 3).

Comparison of MRI or CT, PET or SPECT, and Neuropsychologic Testing Thirteen of the 15 patients (87%) who had a normal MRI or CT scan had an abnormal PET or SPECT scan. All 5 patients (100%) who had an abnormal MRI or CT scan also had an abnormal PET or SPECT scan (table 2).

Fourteen patients (70%) had both temporal lobe defects on PET or SPECT and memory deficits on neuropsychologic testing. Conversely, 6 patients (30%) had discordant findings: 1 patient had temporal lobe defects but no memory deficits, and 5 patients had memory deficits but no temporal lobe defects (table 3).

Seven of the 10 patients (70%) with bilateral temporal abnormalities on PET or SPECT had both verbal and visual memory deficits on neuropsychologic testing. Of the 4 patients with unilateral right temporal lobe abnormalities, 3 (75%) had visual memory deficits and all (100%) had verbal memory Arch Phys Med Rehabil Vol 83, November 2002

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Table 3: Relationship of Temporal Lobe Abnormalities on PET or SPECT and Memory Dysfunction on Neuropsychologic Testing Memory Dysfunction Subject

PET/SPECT Findings

Verbal

Visual

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Bilateral medial Right medial None None Bilateral medial Bilateral medial† Right superior None None Right anterior Bilateral medial Bilateral medial Bilateral medial Bilateral medial† Bilateral inferior and medial None Left posteromedial Bilateral anterior (mostly at tips) Right anterior Bilateral medial

Yes Yes* Yes Yes Yes Yes‡ Yes* Yes Yes Yes㛳 No Yes Yes Yes* Yes Yes Yes* Yes Yes Yes

Yes Yes* Yes Yes Yes No Yes* Yes Yes No No Yes Yes No Yes No No Yes Yes Yes

* Memory difficulties were limited to problems in organizing unstructured and/or complex material. Otherwise, memory functions in this modality appeared intact. † Abnormality may have been normal variant. ‡ Potential motivational problems may have been present. 㛳 Verbal memory inconsistencies “primarily reflect problems in attention and working memory that sometimes interfere with mobilization of apparently intact long-term memory capacities.”

deficits. The patient with a unilateral left temporal abnormality had verbal memory deficits only (table 3).

LOC Versus No LOC Of the 14 patients who sustained an LOC at injury, 3 (21%) had an abnormal MRI or CT scan, 13 (93%) had an abnormal PET or SPECT scan, and all 14 (100%) had some form of neurobehavioral dysfunction on testing. Of the 6 patients who sustained no LOC at injury, 2 (33.3%) had an abnormal MRI or CT scan, 5 (83%) had an abnormal PET or SPECT scan, and 5 (83%) had neurobehavioral dysfunction on testing (table 2).

DISCUSSION In the past, neurosurgeons regarded the postconcussive syndrome as primarily a psychosocial problem.42 Miller43 argued that patients with postconcussive symptoms were exaggerating their disability for psychologic or perhaps financial gain. Merskey and Woodforde44 disputed this explanation, noting that some patients with no possibility for making compensation claims nevertheless showed postconcussion symptoms. Other clinicians have argued that persistent symptoms have a neurologic basis because they occurred earlier in the postinjury period and appear to persist from that time.1 Persistent postconcussive symptoms most likely result from the interaction of both physiologic and psychogenic factors.45,46 Strong support for a physiologic component has come from recent dynamic imaging studies of mild TBI patients with persistent symptoms.30,47-49 Patients in these studies often had frontal and/or temporal lobe abnormalities on PET and/or SPECT, but their static imaging scans were normal. Many Arch Phys Med Rehabil Vol 83, November 2002

patients were evaluated months or years postinjury, suggesting that mild TBI can produce enduring and/or permanent disruptions of brain functioning.

Our study examined a similar group of 20 mild TBI patients who were experiencing persistent postconcussive symptoms for months or even years after their injuries. These patients represent a small subset of mild TBI patients who are more accurately characterized as outliers.17 All 20 patients underwent static imaging, dynamic imaging, and neuropsychologic testing. A comparison of the imaging data showed that dynamic techniques (PET, SPECT) were more sensitive in detecting abnormalities than static techniques (MRI, CT). This finding was consistent with other recent studies.30,32 In our sample, the PET or SPECT scan was abnormal in 3 times as many patients as was the MRI or CT scan. However, all patients with abnormal static images had abnormal dynamic scans.

In contrast, dynamic imaging and neuropsychologic testing were comparable in their general sensitivity to mild TBI. Seventeen of 20 patients (85%) had positive findings on both dynamic imaging and testing, although the location of metabolic defects on imaging and the site(s) of cerebral dysfunction inferred from testing did not always correspond.

Inconsistent correspondence between dynamic imaging and neuropsychologic testing data has been a frustrating finding in a number of studies of TBI patients. For example, Kant et al30 evaluated mild TBI patients with persistent symptoms using SPECT. They noted focal abnormalities in the frontal and/or temporal lobes on imaging scans but found no correlation between these defects and the patients’ neuropsychiatric symptoms or neuropsychologic test scores. Another study by Goldenberg et al50 found no significant relationship between temporal lobe defects on SPECT and performance on memory tests but did find a correlation between frontal lobe defects and executive function deficits.

On the other hand, several studies found good correlations between localized defects on imaging and performance on specific cognitive tasks. Rao et al51 found a close correspondence between PET findings and neurobehavioral test– based inferences about site and extent of brain dysfunction in severe TBI survivors. Wiedmann et al52 also examined severe TBI survivors and found correlations between performance on (1) nonverbal tasks and right anterior temporal defects; (2) verbal recall tasks and left anterior temporal defects; and (3) visual memory tasks and left and right orbitofrontal, right posterior temporal, and right parietal defects. Humayun et al47 found that mild to moderate TBI patients with persistent attention and memory deficits had local metabolic abnormalities on PET, which helped to explain their cognitive deficits. Finally, Gross et al49 found significant correlations between the PET findings, cognitive test results, and behavioral complaints of mild TBI patients.

LOC Versus No LOC Our study also compared the imaging and neuropsychologic test findings of patients who sustained LOC at injury and patients who did not. With respect to static imaging, the results were mixed. A percentage of patients in both subgroups (21% and 33.3%, respectively) had an abnormal MRI or CT scan, suggesting that mild TBI can produce demonstrable structural brain damage whether or not a LOC occurs at the time of injury.

In the functional domain, there was no substantial difference between the 2 subgroups in terms of the absolute number of subjects with abnormal findings on dynamic imaging and neuropsychologic testing (18 vs 19, respectively). In general, pa-

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tients who had abnormal PET or SPECT scans also had abnormal neuropsychologic test results; this was true for 93% of patients who sustained an LOC and 66.6% of patients who did not. Our findings agree with those of Ruff et al17 who found that neither neuropsychologic test findings nor PET findings were substantially (qualitatively) different between mild TBI patients with or without LOC. Neuropathology of Mild TBI A consistent feature of all TBIs is axonal disruption caused by the brain’s exposure to inertial forces. In general, the extent of axonal damage is proportional to the severity of the injury.53 Thus, axonal disruption is the basic pathology even in mild brain injuries.11,54,55 Certain regions of the brain are more vulnerable to inertial injury than others, particularly the frontal and temporal lobes. The selective vulnerability of these regions has been well described in animal studies of moderate and severe injury conducted over the last few decades.

More recent animal studies have looked at the neuropathology of mild to moderate TBI. Earlier studies with monkeys showed that the brainstem was particularly vulnerable to traumatic injury; more recent studies with monkeys and rats have identified the hippocampus in the medial temporal lobe as another vulnerable region. Kotapka et al27 observed hippocampal lesions in a high percentage of monkeys who had received experimentally induced mild TBI. Hicks et al25 found that regional neuronal loss in the hippocampi and disruption of the blood-brain barrier in rats were correlated with significant memory deficits within 48 hours after moderate concussive injury. Smith et al28 found that 2 weeks after mild injury, bilateral loss of dentate hilus neurons was a consistent feature and uniformly associated with memory loss.

The findings of hippocampal vulnerability and memory loss in brain-injured animals are supported by the findings of human clinical studies of memory and learning after TBI. It is well known that disturbances of memory and learning are the most common subjective complaints and most prominent residual cognitive deficits after TBI.18,19 In particular, mild TBI patients have problems in consolidating and recalling new memories.46 Squire and Zola-Morgan20 proposed an explanation for these memory disturbances and their relationship to hippocampal injury. They suggested that the medial temporal lobe memory system performs a crucial role in acquiring and retaining new information about facts and events (declarative memory). This system (which includes the hippocampus and medial temporal lobe structures) is activated at the time of learning and is integral in the process of transforming short-term memory traces into more stable, long-term memory representations.

This process occurs during a lengthy reorganization and consolidation period whereby memories that were initially dependent on the integrity of the medial temporal lobe memory system eventually become independent of it and are assumed by other areas of neocortex.

It is plausible that traumatic injury of the medial temporal cortex produces the memory disorders commonly seen in patients with mild TBI, and such injury may represent the neuropathologic substrate for at least a portion of the complex of residual symptoms and deficits associated with the postconcussive syndrome. We hypothesized that our mild TBI patients would have evidence of temporal lobe injury on dynamic imaging (particularly hippocampal injury in the medial temporal areas) as well as a high proportion of memory deficits on cognitive testing. We found that 15 patients (75%) had abnormal findings in 1 or both temporal lobes on dynamic imaging;

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in 11 of these cases, the medial temporal regions were involved. Moreover, we found that 19 patients (95%) had verbal and/or visual memory deficits on neuropsychologic testing.

Nevertheless, the relationship between temporal lobe defects and memory deficits in our study was not perfect. Some patients had discordant dynamic imaging and memory test findings. Five patients had memory deficits on testing but no temporal lobe defects on PET or SPECT. Three of these 5 patients had defects in nontemporal areas: 2 had frontal defects and 1 had a right parietal defect. The other 2 patients had normal dynamic scans. The performance of these 5 patients on memory tests was obviously compromised by nontemporal factors. In 2 patients, the physiologic disruptions in the frontal lobes may have been responsible. Frontal lobe dysfunction can lead to problems with attention, planning, and intentionality, which can secondarily affect memory functioning. Optimal performance on memory tests depends on the integrity of these capacities as well as more primary memory capacities.

An alternative hypothesis is that the poor memory test performance of these 5 patients was because of the influence of affective factors. It is well known that depressed patients with milder symptoms and self-critical tendencies often show considerable variability in their performance on memory tests and other cognitive tasks (because of fluctuating levels of attention, motivation, and negativism).56 We found that all 5 patients with memory deficits but no temporal lobe abnormalities showed symptoms of depression at the time of their evaluation.

It should be noted that 1 patient had the opposite pattern of results, that is, temporal lobe abnormalities on PET and no memory deficits on testing. This patient reportedly had moderate bilateral hypometabolism in the medial temporal lobes but performed within normal limits on all neuropsychologic tests.

We believe the high percentages of patients in our sample with temporal lobe defects (75%) and memory dysfunction (95%) offer support for the theory of temporal lobe vulnerability in mild TBI. A smaller percentage of patients (30%) had frontal lobe abnormalities as well. These findings are consistent with the results of other dynamic imaging studies that documented frontal and temporal lobe damage in mild TBI patients with persistent symptoms.17,30,48 Moreover, our results are comparable to those of Jacobs et al34 who found that 95% of their patients with persistent postconcussive symptoms and/or clinical signs had abnormal dynamic imaging (SPECT) scans.

Ninety percent of our symptomatic patients had abnormal dynamic imaging (PET, SPECT) scans (compared with only 30% with abnormal MRI or CT scans).

A potential limitation of this study was the considerable variation in time between dates of injury and dates of evaluation among our patient sample. As noted earlier, the mean interval between date of injury and date of dynamic imaging was 586 days (range, 42–2846d), whereas the mean interval between date of injury and date of neuropsychologic testing was 531 days (range, 31–2899d). The extent to which these discrepancies affected the final results of the study is not known. Future studies of this kind should take a more systematic approach to data collection and ensure that sampling times are held constant across all subjects.

The results of this study attest to the value of dynamic imaging techniques in identifying neurophysiologic abnormalities in mild TBI patients that are not detectable with conventional static imaging techniques. PET and SPECT studies performed on sophisticated instruments like the Penn-PET 240H scanner and Picker Prism 3000 SPECT system can reliably and reproducibly demonstrate functional abnormalities in these paArch Phys Med Rehabil Vol 83, November 2002

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tients. This information can be used to determine the extent of damage soon after injury and to evaluate changes over time and after therapeutic interventions such as medical and rehabilitation treatments.

CONCLUSION Patients with mild TBI and persistent postconcussive symptoms have a high incidence of temporal lobe injury (particularly in the medial temporal region). Because the hippocampus and other memory-related structures are located in this area, traumatic injury to these structures could explain the frequent finding of memory disorders in this population. The neuropathologic findings in the medial temporal lobes of animals after experimentally induced mild TBI may represent the same injury shown by dynamic imaging in humans after mild TBI. References 1. Alexander MP. Mild traumatic brain injury: pathophysiology, natural history, and clinical management. Neurology 1995;45: 1253-60.

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