Zita Medical Management 0000 Zita Medical Management2529-05682654-1629 Zita Medical Management http://dx.doi.org/10.36162/hjr.v1i1.22 Research Article traumatic brain injury (TBI); MRI; perfusion imaging; Cerebral blood flow (CBF); neuropsychological testing; memory Cerebral perfusion disturbances in traumatic brain injury: A preliminary study about direct and indirect effects on memory and psychoemotional outcomeCerebral perfusion disturbances in traumatic brain injury Kavroulakis Eleftherios Department of Radiology, University Hospital of Heraklion, Greece 7 2016 21 7 2016 1 1 © 2016 Upon acceptance of an article for publication in Hellenic Journal of Radiology, authors transfer copyright to the Hellenic Radiological Society but they retain the intellectual property rights including research data. 2016

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Cerebral perfusion disturbances in traumatic brain injury: A preliminary study about direct and indirect effects on memory and psychoemotional outcome

Purpose: To investigate possible associations be¬tween hemodynamic changes and psychoemotion¬al/cognitive status in patients with chronic traumat¬ic brain injury (TBI). Methods and Materials: Dynamic Susceptibility Con¬trast Magnetic Resonance Imaging (DSC MRI) perfu¬sion technique was applied to 22 patients with chronic TBI and 21 healthy volunteers. Patients were divided into moderate/severe and mild TBI groups, accord¬ing to clinical syndromes, and administered episod¬ic memory tests and self-report measures of anxiety and depression symptoms. Cerebral blood flow (CBF) and cerebral blood volume (CBV) values were meas¬ured in normal appearing white matter (NAWM) and normal appearing deep gray matter (NADGM) regions bilaterally, including those involved in episodic mem¬ory and psychoemotional status. Results: The two TBI subgroups differed significant¬ly on episodic memory indices. Significantly reduced CBV and CBF values were detected in the moderate/ severe TBI group compared to controls (p<0.001) in bilateral temporal, right frontal and left pari¬etal NAWM and the semioval center. Perfusion re¬duction in the mild TBI group reached significance, compared to controls, only in the left temporal WM (p<0.002). Substantial negative correlations were found between depression/anxiety scores and CBV values in the mesial temporal lobes (MTL) bilateral¬ly. Mediated regression models indicated that the ef¬fect of reduced CBV in the right MTL on verbal ep¬isodic memory was mediated by increased anxiety symptomatology. Conclusion: Patients with moderate/severe chronic TBI displayed widespread reductions in NAWM CBF and CBV. However, only MTL reduced CBV was as¬sociated with verbal episodic memory deficits and increased psychiatric symptomatology. Mediated regression results were consistent with indirect ef¬fects of reduced CBV on episodic memory capacity through increased anxiety symptoms.


Traumatic brain injury (TBI) is a worldwide problem that results in death and disability for millions of people every year, while over 50% of patients experience chron­ic neurological deficits and cognitive and functional im­pairment [1,2]. It is postulated that functional deficits after TBI are partly related to traumatic injury of the neurovascular unit (NVU) -the micro- network that reg­ulates blood flow, vascular permeability and angiogene­sis in the central nervous system (CNS) - caused by BBB disruption, edema and focal tissue hypoxia [3-5]. If NVU is not rapidly restored, further local injury is induced [4] with ongoing hypoperfusion and neurodegeneration [5, 6]. These processes apparently take place not only following severe TBI, but, also, after moderate or mild chronic TBI patients [7].

Conventional MRI (i.e., T1SE, T2TSE, FLAIR and GRE se­quences), although very sensitive for the detection of TBI lesions, fails to reveal the true extent of structural and functional damage and commonly underestimates Dif­fuse Axonal Injury (DAI) and atrophy [8]. On the contra­ry, advanced MRI techniques (i.e, Diffusion Tensor Imag­ing, perfusion imaging and functional MRI) provide more accurate tools to measure and monitor neurovascular in­tegrity and function, aspiring to improve the understand­ing of TBI pathophysiology and influence rehabilitation planning in chronic TBI patients [9-12]. In particular, per­fusion MRI provides accurate quantitative hemodynam­ic indices, such as Cerebral Blood Flow (CBF) and Cerebral Blood Volume (CBV), non invasively, and has been proven a valuable tool for both clinical diagnosis and intervention planning [13-16]. Recent Arterial Spin Labeling (ASL) MR perfusion studies have reported widespread reduction in CBF in both normal appearing white matter (NAWM) and normal appearing deep gray matter (NADGM) of acute and chronic TBI patients, indicating diffuse vascular damage and global ischemia [17-23]. Dynamic susceptibility con­trast (DSC) MR perfusion imaging allows the assessment of cerebral hemodynamics, by estimating tissue concentra­tion versus time curves after bolus injection of intravascu­lar contrast agents [24-27] and has been used successful­ly to detect and quantify regional perfusion in acute and chronic TBI [28-30].

An important step in determining the clinical signif­icance of regionally reduced hemodynamic activity en­tails establishing associations between localized defects on imaging and injury severity, as well as performance on specific cognitive tasks. Published studies directly assessing measures of cerebral blood flow/volume and/ or metabolism and cognitive outcomes in sufficiently large samples of TBI patients are scarce. Wiedmann et al. [31] were among the first to document associations between SPECT-CBF abnormalities in the temporal lobes and memory deficits in 16 chronic TBI patiens. Umile et al. [32] reported a qualitative link between presence of memory deficits and reduced blood flow/metabolism (using PET or SPECT) in the temporal lobes in the sub­acute phase post mild TBI in 20 patients. Interesting­ly, several patients demonstrated abnormal findings in PET/SPECT accompanied by cognitive deficits in the ab­sence of structural MRI abnormalities. It should be not­ed, however, that other studies have failed to identify re­lations between regional cerebral metabolism (PET) [33] or regional cerebral blood flow (SPECT) [34] and cogni­tive performance in chronic TBI patients.

CBF measurements in the chronic phase post TBI may serve as an indicator for the mechanism underlying cog­nitive impairment, as well as for the comprehension of the pattern and degree of neural and/or functional re­covery. Sometimes, however, neuroimaging findings are further complicated by failure to take into account fre­quently occurring psychoemotional difficulties, such as symptoms of depression and anxiety [35]. Such changes may be secondary to physical disability and/or cognitive deficits that affect functionality and post-injury adapta­tion [36]. An alternative, albeit non-mutually exclusive, account implicates direct effects of neuronal changes in brain regions involved in the generation and/or regu­lation of emotional states and responses. These regions include the mesial portion of the temporal lobe [37], the dorsolateral prefrontal cortex [38], and the anterior sec­tion of the cingulate gyrus [23, 39]. In this context, al­tered brain function in specific key regions may cause both cognitive and emotional changes, with the latter further impacting the patient’s capacity to perform de­manding cognitive tasks [40, 41]. The chief goal of the present preliminary study was to explore the association between hemodynamic distur­bances in TBI patients and injury severity, predicting a progressive reduction in CBF and CBV between patients in the chronic phase post mild TBI and chronic moder­ate/severe TBI patients. A secondary goal was to inves­tigate the functional significance of perfusion chang­es detected in TBI patients by examining the pattern of associations between perfusion indices and episodic memory capacity, in view of extant data on memory dif­ficulties in chronic TBI patients [42, 43]. Both direct and indirect effects (through psychoemotional variables) of perfusion on episodic memory indices were examined via mediated regression analyses. These models attempt­ed to account for commonly reported, co-occurring cog­nitive deficits

and psychoemotional difficulties among TBI patients.

Materials and Methods

2.1 Subjects

Patients with a history of TBI were recruited through the medical records of Neurosurgery Clinic of the Uni­versity Hospital of Heraklion-Crete. To be included in the study, patients had to be between 20 and 70 years, and have a history of non-penetrating TBI, at least one year before, without neurosurgical intervention. Poten­tial participants were excluded if they had a prior his­tory of pre-morbid neurological or psychiatric disease, current history of substance abuse, or if they were cur­rently receiving psychoactive medications other than anticonvulsants.

The final sample included 22 patients (M/W=20/2), aged 37.6 ± 13.6 years (range 21 to 69) who had sustained TBI on average 31.3 ± 14.4 months ago (range 13 to 72 months) (Table 1). Head injury severity was assessed us­ing the Glasgow Coma Scale (GCS) after resuscitation at the time of injury and patients were initially categorized into mildly, moderately and severely injured subgroups [44]. In order to increase subgroup size for subsequent perfusion analyses, patients were reassigned to two TBI severity groups: Mild (n=8) and moderate/severe (n=14). The two TBI severity subgroups were comparable on age, education, and time post injury (p>.3).

Hemodynamic data from 21 healthy controls (4 men and 17 women, mean age=35.5 ± 6.2 years) were also ob­tained for comparison. The study was approved by the University Hospital Ethics Committee and written in­formed consent was obtained from all patients, after be­ing briefed on study details.2.2 Magnetic Resonance Imaging Acquisition and Data Analysis

Brain MRI examinations were performed on a clinical 1.5 T whole-body superconducting imaging system (Vision/ Sonata, Siemens/Erlangen), equipped with high perfor­mance gradients (Gradient strength: 40mT/m, Slew rate: 200mT/m/ms) and a two-element circularly polarizedhead array coil. The conventional imaging protocol was comprised of a 3D T1-w sequence (MPRAGE, TR 1,570/ TE 1.73 ms, 160 axial slices), and contiguous 4 mm thick axial sections of a T2TSE (TR/TE=5,000/98 ms), a TUR­BO-FLAIR (TR/TE/TI=9,000/120/2,600 ms) and a T2*GRE (TR/T*=615/24 ms) sequence.

The T2* DSC-MRI was performed utilizing a 2D sin­gle shot multislice Gradient Echo Echo Planar Imaging (GREEPI) sequence (TR/TE/FA: 1,500 ms/40 ms/30o, BW: 2,442 Hz/pixel, Echo spacing: 0.47 ms and Echo Planar Imaging (EPI) factor 64). Twenty consecutive slices of 4 mm slice thickness and 1.5 mm interslice gap with 50 dynamic acquisitions were obtained. Immediately after the end of the fifth dynamic acquisition, a bolus of 0.1 mmol/kg body weight of gadobutrol (Gadovist, Schering AG, Germany) was injected intravenously, at an injection rate of 4 mL/sec immediately followed by a bolus injec­tion of 15 mL of saline at the same rate. Post processing of the perfusion data was performed using a dedicated software (NordicNeuroLab AS, Bergen, Norway). The ar­terial input function was calculated by manually defin­ing a major artery (usually MCA) and parametric maps of relative CBV and CBF values were automatically created.

Chronic posttraumatic lesions were identified on T2, FLAIR and GRE sequences and categorized by lobe (fron­tal, temporal, parietal) and type (contusion or DAI).

CBV and CBF values of NAWM and NADGM areas were calculated in two partially overlapping series of regions. One set comprised 20 sections of the brain including NAWM in the periventricular region, semioval center, forebrain (in the frontal, parietal, temporal, and occipi­tal lobes), splenium and genu of the corpus callosum, and NADGM in the thalami, putamen, and caudate nuclei. In order to enhance measurement fidelity, three CBV and CBF measurements were obtained from each of the dif­ferent NAWM and NADGM areas, which were then aver­aged. Two measurements were obtained from each cau­date nucleus, due to its small size. All ROIs were fixed in size (radius of 2 mm) and were placed at the bolus peak of the GRE EPI images, which show the vessels to better ad­vantage and thus vascular structures were avoided. From the GREEPI images, ROIs were automatically transferred to the CBV and CBF maps. In order to compare between different subjects, the calculated relative CBV and CBF values were normalized for each patient with respect to the respective values of the cerebellum WM.

A second set of CBV and CBF measurements were ob­tained in the NAWM of seven sublobar Regions of Inter­est (ROIs) in each hemisphere, which are suspected to play a key role in the brain circuits responsible for epi­sodic memory and emotional processes, including anx­iety and depression: Anterior and mesial temporal lobe (BA 20,36,38), inferior (BA44/45/47), middle (BA46/9), and superior frontal gyri (BA 8/9), inferior parietal lob­ule (BA 39), and cingulate gyrus (BA32).

2.3 Neuropsychological and Psychoemotional Measures

Patients were administered a battery of neuropsycholog­ical tests primary targeting memory skills. Short-term and working verbal memory was assessed with the Mem­ory for Digits Forward and Reverse subtests, respectively from the Greek Memory Scale (GMS) [45], adapted for re­search purposes in Greek [46]. Secondary verbal episod­ic memory was assessed with the GMS Passage Memory subscale and secondary visual episodic memory with the modified Taylor Complex Figure (TCF) test [47]. Norma­tive data were available on a sample of 550 native Greek individuals aged 16-65 years stratified by educational level and geographical origin, permitting computation of age -and education- adjusted standard scores for six subgroups (16-38 and 39-60 years old with 0-9, 10-12 and 13+ years of formal education).

Psychoemotional variables (depression and anxiety self-ratings) were also assessed, using the Greek adap­tations of the Center for Epidemiology Studies Depres­sion Scale (CESD) [48] and the Spielberger Trait Anxiety Inventory (STAI-B) [49].

2.4 Statistical analysis

TBI subgroup comparisons on demographic, clinical and neuropsychological data were performed via one-way ANOVAs or Pearson chi-square tests for propor­tions, when appropriate (evaluated at α=0.05, two tailed). Group differences on normalized, regional perfusion val­ues were assessed using one-way ANOVAs, separately for each brain section and ROI. All tests were evaluated at a Bonferroni-adjusted α=0.05/20 (brain sections)=0.0025, or α=0.05/14 (ROIs)=0.0035, accordingly. Group served as the between subjects variable with three levels: Con­trols (n=21), Mild TBI (n=8), Moderate/Severe TBI (n=14).

Associations between perfusion measures and clinical, cognitive, or psychoemotional variables were assessed through Pearson correlation coefficients for the entire group of TBI patients. With the exception of anxiety and depression scores all other neuropsychological measures were converted to age -and education- adjusted z scores based on Greek population norms.

Finally, mediated regression models assessed (a) di­rect effects of perfusion on episodic memory indices and (b) indirect effects of psychoemotional status as media­tors in the relationship between perfusion and memory skills. The basic mediated regression model is illustrat­ed in Fig. 4. We used SPSS macros developed by Hayes (2013; model 4) to assess simple mediation effects. The M (ediator) variable (CESD or STAI-B raw score) was es­timated as a function of normalized CBF or CBV value (X) in a given ROI plus an appropriate intercept using the fol­lowing equation:

M=iM + αX + eM (Eq 1)

Individual scores on the outcome variable Y (raw ep­isodic memory score) were estimated as the sum of the corresponding intercept iy, the direct effect of the per­fusion measure on Y controlling for any indirect effects (c’1) and the indirect effect of the perfusion measure on Y according to the following equation:

Y=iy + c’1X + bM + ey (Eq 2)

The multiplicative term bM was computed by multi­plying the α and b paths. The program generates boot­strapped confidence intervals for all direct and indirect effects, thus reducing the impact of potential normali­ty violations on significance testing. All statistical analy­ses were performed with SPSS version 20 (SPSS Inc., Chi­cago, IL, USA).

Table 1
Table 1. Clinical, demographic and neuropsychological information on the patients
N/Mean ± SD Range
Gender Men 20 Women 2
TBI Severity Mild 8 Moderate 8 Severe 6
Trauma type MVA 14 Fall 8
Age (years) 37.6 ± 13.6 21 to 69
Education (years) 11.18 ± 4.3 1 to 20
Months post injury 31.3 ± 14.4 13 to 72
GCS 10.7 ± 3.4 3 to 15
Digits Forward (z) -0.18 ± 1.2 -3.1 to 2.1
Digits Reverse (z) -0.72 ± 1.1** -3.2 to 0.9
PM-Immediate -1.11 ± 1.0† -3.1 to 0.7
PM-Delayed -1.4 ± 1.3† -3.8 to 0.8
PM-Retention -1.6 ± 2.7** -6.8 to 3.6
PM-Recognition -2.17 ± 2.7† -6.4 to 1.2
TCF-copy 0.02 ± 1.1 -1.2 to 1.1
TCF-Memory -0.74 ± 1.3** -2.9 to 2.2
CESD 20.3 ± 16.2 2 to 57
STAI-B (Trait Anxiety) 41.2 ± 13.7 21 to 66Abbreviations; GCS: Glasgow Coma Scale, CESD: Center for Epi­demiological Studies Depression scale, STAI-A: State-Trait Anxi­ety Inventory Form Y, GAMA: General Ability Measure for Adults, MVA: Motor Vehicle Accident, TCF: Taylor Complex Figure Test. Note; Significant difference from age -and education- adjust­ed population mean: ** p=0.01, † p=0.001

3.1 Cognitive and psychoemotional profiles

As shown in Table 1, patients as a group performed sig­nificantly below age -and education- adjusted popula­tion means on Digits Reverse, Immediate and Delayed Passage recall and recognition, and TCF-Memory scores .

The two TBI severity subgroups differed significantly on episodic memory indices (Passage Memory Immediate re­call, F[1,21]=9.13, p=0.007, η2=0.325, Passage Memory De­layed recall, F[1,21]=10.58, p=0.004, η2=0.358, and Passage Memory Recognition, F[1,21]=6.39, p=0.02, η2=0.252). Al­though patients with moderate/severe TBI had the ten­dency to report higher frequency of depression and anx­iety symptoms than patients following mild TBI, this difference did not reach significance (p>0.13).

3.2 Comparison between controls and TBI subgroups on perfusion measures

Main effects of Group on CBF measured in the 20 NAWM and NADGM areas meeting the Bonferroni-corrected al­pha level of 0.003, were found in the temporal lobe WM and semioval center bilaterally and also in the right fron­tal and left parietal WM (Table 3, Fig. 1a). Significant group main effects on CBV were found in the temporal lobe, bilaterally, and in the right frontal and periven­tricular WM (Table 3, Fig. 1b). There are no significant group main effects on CBV or CBF of NADGM areas.In all cases the linear trend was also significant (p>0.001) in the absence of a significant quadratic trend (p>0.05), suggesting a progressive decrease of perfusion between controls, mild, and moderate/severe groups. Al­though TBI subgroup sizes were too small to substanti­ate differences between the two TBI subgroups, pairwise comparisons supported this hypothesis by revealing sig­nificantly reduced perfusion measures in the moderate/ severe group compared to controls (p<0.001 in all cases). Conversely, perfusion reduction in the mild TBI group compared to controls reached significance at the Bon­feroni-corrected alpha level of 0.002 only in the left tem­poral WM.Additional perfusion measurements targeting WM in the sublobar regions known to be involved in episod­ic memory and psychoemotional status, shown group main effects and corresponding linear trends (p<0.001) for CBF in medial temporal and cingulate WM bilateral­ly, and in the right anterior temporal and middle fron­tal regions (Table 4, Fig. 2a). Group main effects on CBV were more widespread as they were found, addi­tionally, in the angular gyrus, bilaterally and further in the right inferior frontal gyrus (Table 4, Fig. 2b). Pair­wise comparisons revealed significantly (p<0.002) re­duced CBF and CBV in controls compared to the moder­ate/severe TBI group in all regions. Reduced perfusion in mild TBI vs. controls was restricted to a single region (right IFG) for CBV.

3.3. Correlations between MRI measures and clinical variables

Pearson correlations further suggested that CBF in the left MTL (r=0.500, p=0.021) and nearby ATL (r=0.478, p=0.028) increased with time post injury across TBI sub­groups (CBV in these regions and either perfusion meas­ure in predefined WM sections did not correlate signif­icantly with clinical variables). GCS did not correlate significantly (r<0.25) with CBF, CBV or with the type (contusion/DAI) and lobe (temporal/frontal in each hemisphere) of structural abnormalities.

3.4. Correlations between perfusion measures and psychoemotional/cognitive status

Weak correlations were found among CBV values in the MTL bilaterally and the MRI-detectable lesions (Table 5). Substantial negative correlations were found between depression/anxiety scores and CBV values in the MTL, bilaterally (Table 5) indicating that higher CBV values were associated with lesser intensity/frequency of psy­choemotional symptoms. These moderate/strong linear associations are illustrated in Fig. 3.As shown in Table 5, however, psychoemotional vari­ables also correlated significantly with episodic memo­ry scores (immediate recall of Story B) although the bi­variate, zero-order correlation between the latter and Right MTL CBV was weaker. The possibility of indirect effects of perfusion disturbance on episodic memory through elevated psychoemotional symptoms was fur­ther explored in mediation regression analyses, predict­ing episodic memory raw scores from CBV via CESD or STAI-B scores. The model tested is illustrated in Figure 4 which displays unstandardized regression coefficients for direct effects and corresponding p values in paren­theses. Importantly, whereas the direct effect of CBV on memory was not significant, the indirect effect reached significance (b=1.74, SE=0.962, CI=0.146 to 3.94, z=2.036, p=0.042) supporting the hypothesis that elevated anxie­ty symptoms were directly associated with reduced CBV in the right MTL, which in turn resulted in suppressed capacity to memorize verbal material for subsequent re­call. The indirect effect remained significant after con­trolling for the presence of cerebral contusion or DAI in the right temporal lobe.

3.5. Correlations between structural abnormalities and psychoemotional/cognitive status

Whereas correlations between structural MRI abnormal­ity indices and cognitive variables did not exceed r= -0.25 (p>0.3), significant positive associations were found with psychoemotional status. In particular presence of con­tusion in the right temporal lobe was a significant pre­dictor of CESD score (r=0.563, p=0.01). The association between right temporal contusion and anxiety did not reach significance (r=0.380, p=0.09).

Multiple regression analyses with CESD as the depend­ent variable, revealed that right MTL CBV (β= -0.527, t= -2.605, p=0.021) and right temporal contusions (β=0.460, t= -2.332, p=0.040) made significant independent con­tributions to CESD scores (R2=0.402, SE=13.05, p=0.016). Conversely right MTL CBV remained a significant pre­dictor of STAI-B scores after controlling for presence of contusion in the right temporal lobe (R2=0.390, SE=11.33, p=0.019; β= -0.613, t= -3.084, p=0.007), whereas the contri­bution of contusions controlling for CBV did not reach significance (β=0.05, p>0.8).

Regression models, such as the one presented, in Fig­ure 4 failed to reveal significant mediation (by STAI-B or CESD scores) of the association between structural brain abnormalities and cognitive variables.

Table 2

Table 2 presents individual patient data on the loca­tion of MR -detectable anatomic abnormalities, in relation to significant cognitive deficits or psychoemotional difficulties (as defined by scores in excess of 1.5 SD below the respective age -and education-adjusted population means). Episodic memory deficits (on immediate and/or delayed recall and recognition measures) were noted in 63.6% of patients and working memory deficits in 36.4%, whereas significant symptoms of depression and/or anx­iety were reported by 27.3% of patients.

Mild TBI patients are less likely to experience cogni­tive deficits spanning more than one domain. The two groups (mild vs. moderate/severe TBI were largely com­parable on the presence of structural abnormalities (cer­ebral contusion or DAI in the temporal and frontal lobes; p>0.5 for all comparisons). ­

Table 2. Individual demographic, clinical, imaging and neuropsychiatric data for TBI patients
Age (years) Education (years) GCS TBI Group Duration (months) Lesion Neuropsychiatric impairment
45 17 14 Mild 22 RT frontotemporal contusion Episodic memory (delayed)
42 8 12 Moderate 35 RT frontotemporal contusion Episodic memory (immediate/delayed), execu­tive, anxiety, depression
21 13 13 Mild 23 Bilateral temporal contusion anxiety, depression
30 6 10 Moderate 48 RT parietal, bilateral frontal DAI Episodic memory (immediate/delayed)
58 10 13 Moderate 24 none Episodic memory (immediate/delayed)
36 13 12 Moderate 23 Bilateral frontal contu­sion, RT frontal DAI Executive
23 10 7 Severe 26 Bilateral frontal contu­sion, RT frontal DAI Episodic memory (immedi­ate/delayed), anxiety
29 11 12 Mild 15 Bilateral frontal DAI Executive
40 12 14 Mild 50 LT temporal contusion anxiety
38 16 7 Severe 25 LT temporo-occipital contusion and DAI, RT temporal and CC DAI Episodic memory (immediate/delayed)
23 12 6 Severe 18 LT frontal DAI Episodic memory (immedi­ate/delayed), executive
48 16 15 Mild 26 LT temporal & bilateral frontal contusion Episodic memory (delayed)
40 20 3 Severe 33 none none
53 1 12 Moderate 57 LT frontotemporal contusion, bilateral frontal DAI Episodic memory (immedi­ate/delayed), executive
29 10 11 Moderate 31 none Episodic memory (immedi­ate/delayed), executive
26 9 4 Severe 13 none Episodic memory (immedi­ate/delayed), executive
59 8 13 Mild 33 none none
22 14 8 Severe 27 LT Frontoparietal DAI Episodic memory (immediate)
29 13 11 Moderate 24 Bilateral frontal & LT temporal DAI Episodic memory (delayed)
69 6 13 Mild 23 LT temporal contusion anxiety
23 7 13 Mild 72 none none
44 14 12 Moderate 42 none Episodic memory (delayed), executive, depression
Table 3

* Significant at Bonferroni-corrected alpha = 0.002. L/R: Left and Right hemispheres, respectively

Table 3. Perfusion (CBF and CBV) differences between controls and TBI subgroups in NAWM
CBF F p η2 C>Mild C>Mod/Severe
Temporal (L) 12,657 0.000 0.388 0.001* 0.0001*
Temporal (R) 6,586 0.003 0.248 0.014 0.002*
Frontal (R) 8,310 0.001 0.294 0.005 0.001*
Parietal (L) 8,002 0.001 0.286 0.025 0.0001*
Semioval Center ((L) 7,861 0.001 0.282 0.006 0.001*
Semioval Center (R) 8,428 0.001 0.296 0.003 0.001*
CBV F p η2 C>Mild C>Mod/Severe
Temporal (L) 12,010 0.000 0.375 0.005 0.0001*
Temporal (R) 7,334 0.002 0.268 0.02 0.001*
Frontal (R) 8,847 0.001 0.307 0.006 0.0001*
Periventricular (R) 9,983 0.000 0.333 0.014 0.0001*
Table 4

* Significant at Bonferroni-corrected alpha =0.002

Table 4. Perfusion (CBF and CBV) differences between controls and TBI subgroups: ROI analyses
CBF F p η2 C>Mild C>Mod/Severe
ATL (R) 7.52 0.001 0.278 0.039 0.0001*
MTL (L) 8.41 0.001 0.301 0.006 0.001*
MTL (R) 10.42 0.0001 0.348 0.035 0.001*
MFG (R) 8.86 0.001 0.313 0.043 0.0001*
Cingulate (L) 9.87 0.0001 0.317 0.028 0.0001*
Cingulate (R) 9.28 0.0001 0.330 0.024 0.0001*
CBV F p η2 C>Mild C>Mod/Severe
ATL (R) 9.77 0.0001 0.278 0.004 0.002*
MTL (L) 7.77 0.001 0.285 0.02 0.001*
MTL (R) 10.16 0.0001 0.343 0.005 0.002*
IFG (R) 12.70 0.0001 0.394 0.002* 0.0001*
MFG (R) 10.83 0.0001 0.357 0.004 0.001*
Cingulate (L) 9.36 0.0001 0.319 0.021 0.0001*
Cingulate (R) 7.85 0.001 0.282 0.017 0.001*
Angular (L) 8.53 0.001 0.300 0.008 0.002*
Angular (R) 6.55 0.003 0.247 0.025 0.002*
Table 5 Figure 1 Figure 2 Figure 3 Figure 4 Discussion

Traumatic forces initiate a cascade of neurovascular re­sponses and perfusion changes that play a significant role in the establishment of chronic TBI structural and functional abnormalities and the development of post­traumatic morbidity [3-5]. Neuroimaging studies have shown hypoperfusion acutely after TBI in humans [7, 17, 34, 50, 51] and experimental TBI in rats [52]. Several in­vestigators have demonstrated cerebral blood flow (CBF) deficits in moderate to/severe TBI, weeks to years af­ter trauma [19,20, 23] while regional hypoperfusion has, also, been reported in chronic mild TBI [18, 21, 22, 30, 53-62 ]. Global or regional hypoperfusion in the chronic phase is probably the result of imbalanced cerebrovas­cular autoregulation and damaged NYU. There is further evidence of posttraumatic venous damage, even at much lower stretching and shearing forces, that could cause impaired perfusion [63], especially in mild TBI. Our perfusion results showing hypoperfusion in tem­poral, frontal, periventricular and semioval center WM of moderate/severe TBI patients and in particular tem­poral and frontal WM regions in the mild TBI group, are in agreement with perfusion abnormalities reported by other neuroimaging techniques. In the current study re­duced perfusion was found, additionally, in temporal and frontal regions and the cingulate NAWM bilaterally, re­gions known to be involved in episodic memory, consist­ent with previous studies [19-23, 30, 56, 59, 60, 61, 64].

Earlier perfusion studies in chronic TBI, utilizing PET or SPECT, demonstrated several regions of hypoper­fusion, particularly in the frontal and temporal lobes, which significantly correlated with neuropsychological or neurological [56-59, 62, 64-67]. Both of these imaging modalities involve radiation exposure and suffer from low spatial resolution, while, PET is, also, costly and dif­ficult to use in clinical practice. ASL MR perfusion imag­ing studies have revealed similar changes in global and regional CBF in TBI patients across severity subgroups. Patients with chronic moderate-to-severe TBI have de­creased regional perfusion in the thalamus, posterior cingulate and frontal cortex, while reduced CBF has also been found in mild TBI, in bilateral frontotemporal re­gions [18-23, 60].

The DSC MR perfusion technique has been widely used in clinical practice to obtain relative perfusion measure­ments in a variety of neurological diseases [15, 16, 68] . Its application in TBI patients may significantly contrib­ute to the understanding of the pathophysiology of head injury, and potentially in identifying clinically relevant predictive markers of treatment effects. Using DSC-MRI widespread hypoperfusion has been shown in acute ex­perimental TBI in rats [52] and in acute human moder­ate to severe TBI cases [29]. Reduced rCBF has also been reported in the cingulated gyrus, cuneus and temporal lobe in chronic mild TBI patients [30] and symptomatic sports-related concussion patients [6]. To our knowledge the current study is the first to report DSC-MRI results in chronic patients over a wide range of TBI severity. A progressive decrease of perfusion between controls, mild, and moderate/severe groups was noted, suggesting chronic microvascular changes that may underlie persis­tent post-traumatic symptoms or functional abnormali­ties without apparent neurological deficits.

Associations between reduced perfusion in the left temporal lobe and verbal memory decline found in the present study are consistent with earlier findings es­tablishing links between left temporal damage [69, 70] and reduced regional cerebral blood flow/metabolism [31, 32] with verbal memory deficits in TBI patients. Learning and memory difficulties are among the most common deficits observed in TBI and are often present even following mild TBI [42, 43]. Elevated levels of anx­iety and depressive symptomatology are also common in TBI although the causes of such symptoms are still debated [71, 72]. The current data are consistent with a common neurophysiological substrate for both memo­ry and psychiatric symptoms involving dysfunction of circuits comprised to a large extent by medial temporal lobe structures. Thus the left hippocampus and parahip­pocampal cortex are known to be critically involved in the acquisition of new verbal episodic memories. These structures serve a pivotal role in the consolidation of mnemonic traces [73, 74] through concurrent activity in lateral temporal neocortical regions. These regions are also key components of the medial limbic circuit which is crucial for the generation of emotional responses to external and internal stimuli and in the intrinsic regu­lation of emotions. Limbic dysfunction has been suggest­ed as one of several neurophysiological correlates of de­pression [75]. Our findings concur with earlier results in highlighting a direct link between structural damage incurred in right temporal lobe and psychiatric seque­lae of TBI (especially depression). In a similar vein, the significant bivariate correlations between bilateral MTL dysfunction (as indicated by reduced CBV) and both de­pression and anxiety symptomatology are not surpris­ing. To our knowledge the indirect association between reduced left temporal lobe perfusion and verbal mem­ory performance through increased psychiatric symp­tomatology has not been formally explored before. This model, however, is supported by growing evidence sug­gesting a causal link between depressive symptomatolo­gy and accelerated age-related cognitive decline [76, 77].

Studies establishing links between regional perfusion and psychiatric symptoms are limited. Recently, reduced CBF in the posterior hippocampus was found to be associ­ated with increased depressive symptomatology among patients with chronic heart failure [78]. In TBI, howev­er, the limited thus far investigations implicate struc­tural prefrontal damage in the etiology of depressive symptomatology post TBI [35]. Associations between left temporal structural damage and anxiety symptoms

in chronic TBI have been reported by at least one study [79] consistent with the crucial role of mesial temporal structures (amygdala, hippocampus, parahippocampal gyrus) [80, 81].

The frequency of significant memory deficits among chronic mild TBI patients in our sample is higher than what is typically reported in previous studies and me­ta-analyses [82]. This could be related to contamina­tion of the mild TBI subgroup by moderate TBI cases, a hypothesis further supported by the relatively high frequency of MR-detectable structural abnormalities among patients with GCS scores consistent with mild TBI.

Notably, measures of immediate verbal episodic re­call were significantly related to perfusion measures and depression/anxiety symptoms, whereas delayed recall indices did not. Although the sensitivity of im­mediate episodic memory indices has been reported in neuropsychological studies of TBI [70, 83], the present results highlight the increased susceptibility of meas­ures of the initial coding and retrieval of verbal infor­mation to anxiety and depression in TBI [84] and to a variety of other neuropsychiatric conditions [85, 86, 87]. Stronger links between measures of left MTL in­tegrity and immediate (as opposed to delayed) verbal memory have also been reported in elderly persons with depression [88].

An important limitation of DSC-MRI in clinical prac­tice is the relative rather than absolute quantification of CBF, due to lack of a reliable arterial input function (AIF) [89]. On the contrary, ASL perfusion MRI offers absolute quantification of CBF, without usage of contrast agent, but suffers from a low signal-to-noise ratio and has low­er spatial resolution compared with DSC [90]. Similarly to others perfusion techniques, DSC-MRI has limitations in evaluating and interpreting post traumatic hypoper­fusion, due to the strong association between CBF meas­urements and cerebral metabolic demands. Thus, the observed CBF reduction may be the result not only of a primary vascular injury but of neuronal or axonal injury, as well, that reduce cerebral metabolic demand. Recent studies combining MRI with the Blood Oxygen Depend­ent (BOLD) signal in response to hypercapnia challenge provide more direct measures of cerebral vascular inju­ry by assessing of cerebral vascular reactivity/reverse (CVR) [29]. Finally, this preliminary study has the limi­tation of the small sample, especially of mild TBI patients and the results should be interpreted with caution. Fur­ther perfusion and neuropsychological measurements in a larger number of chronic patients over a wide range of TBI severities may enhance the sensitivity of the meth­od in detecting more subtle and complex associations between perfusion measurements and neuropsychiat­ric variables.

5. Conclusion

Despite the study limitations outlined above, our prelim­inary results highlighted robust and widespread reduc­tions in both CBF and CBV in NAWM in the chronic phase after moderate/severe TBI. Smaller, yet detectable, were CBF/CBF reductions found among patients with mild TBI, in spite of the small size of this subgroup. The specificity of the present results is further attested by the anatomic plausibility of perfusion-behavior associations, identify­ing reduced perfusion in the MTL as the sole significant correlate of both verbal episodic memory deficits and in­creased psychiatric symptomatology. Finally, mediated regression analyses are consistent with complex models accounting for the emergence and parallel course of cog­nitive and psychoemotional sequelae of head trauma. R

Conflict of interest:

The authors declared no conflicts of interest.


1. Brazinova A, Rehorcikova V, Taylor MS, et al. Epide­miology of traumatic brain injury in Europe: A living systematic review. J Neurotrauma 2018; doi: 10.1089/neu.2015.4126.

2. Thurman DJ, Alverson C, Dunn KA, et al. Traumatic brain injury in the United States: A public health per­spective. J Head Trauma Rehabil 1999; 14(6): 602-615.

3. Kenney K, Amyot F, Haber M, et al. Cerebral Vascu­lar Injury in Traumatic Brain Injury. Exp Neurol 2016; 275(3): 353-366.

4. Shlosberg D, Benifla M, Kaufer D, et al. Blood-brain barrier breakdown as a therapeutic target in trau­

matic brain injury. Nat Rev Neurol 2010; 6(7): 393-403.

5. Del Zoppo GJ .Toward the neurovascular unit. A jour­ney in clinical translation: 2012 Thomas Willis Lec­ture. Stroke 2013; 44(1): 263-269.

6. Bartnik-Olson BL, Holshouser B, Wang H, et al. Im­paired neurovascular unit function contributes to persistent symptoms after concussion: A pilot study. J Neurotrauma 2014; 31(17): 1497-1506.

7. Metting Z, Spikman JM, Rödiger LA, et al. Cerebral perfusion and neuropsychological follow up in mild traumatic brain injury: Acute versus chronic distur­bances? Brain Cogn. 2014; 86: 24-31.

8. Rugg-Gunn FJ, Symms MR, Barker GJ, et al. Diffusion imaging shows abnormalities after blunt head trauma when conventional magnetic resonance imaging is normal. J Neurol Neurosurg Psychiatry 2001; 70: 530-533.

9. Kinnunen KM, Greenwood R, Powell JH, et al. White matter damage and cognitive impairment after trau­matic brain injury. Brain 2011; 134(2): 449-463.

10. Sharp DJ, Ham TE Investigating white matter inju­ry after mild traumatic brain injury. Curr Opin Neu­rol 2011; 24(6): 558-563.

11. Wada T, Asano Y, Shinoda J. Decreased fractional ani­sotropy evaluated using tract-based spatial statistics and correlated with cognitive dysfunction in patients with mild traumatic brain injury in the chronic stage. Am J Neuroradiol 2012; 33(11): 2117-2122.

12. Warner MA, Marquez de la Plata C, Spence J, et al. As­sessing spatial relationships between axonal integri­ty, regional brain volumes, and neuropsychological outcomes after traumatic axonal injury. J Neurotrau­ma 2010; 27(12): 2121-2130.

13. Zaharchuk G. Theoritical basis of hemodynamic MR imaging techniques to measure cerebral blood vol­ume, cerebral blood flow, and permeability. Am J Neuroradiol 2007; 28: 1850-1858.

14. Alsop D. Perfusion imaging of the brain. In: Edelman RR, Hesselink JR, Zlatkin MB, Crues JV, editors. Clin­ical magnetic resonance imaging, 3rd ed. Philadel­phia, PA: Saunders Elsevier; 2006. pp 333-376.

15. Pathak AP, Schmainda KM, Ward BD, et al. MR-de­rived cerebral blood volume maps: Issues regarding histological validation and assessment of tumor an­giogenesis. Magn Reson Med 2001; 46: 735-747.

16. Mair G, Wardlaw JM. Imaging of acute stroke prior to treatment: Current practice and evolving tech­niques.Br J Radiol 2014; 87(1040): 201-216.

17. Doshi H, Wiseman N, Liu J, et al. Cerebral hemody­namic changes of mild traumatic brain injury at the acute stage. PLoS One 2015; 10(2).

18. Ge Y, Patel MB, Chen Q, et al. Assessment of thalamic perfusion in patients with mild traumatic brain in­jury by true FISP arterial spin labeling MR imaging at 3T. Brain Inj 2009; 23: 666-674.

19. Kim J, Whyte J, Patel S, et al. Resting cerebral blood flow alterations in chronic traumatic brain injury: An arterial spin labeling perfusion fMRI study. J. Neu­rotrauma 2010; 27(8): 1399-1411.

20. Kim J, Whyte J, Patel S, et al. A Perfusion fMRI Study of the Neural Correlates of Sustained-Attention and Working-Memory Deficits in Chronic Traumat­ic Brain Injury. Neurorehabilitation and Neural Repair 2012; 26(7): 870-880.

21. Wang Y, West JD, Bailey JN, et al. Decreased cere­bral blood flow in chronic pediatric mild TBI: An MRI perfusion study. Dev Neuropsychol 2015; 40(1): 40-44.

22. Grossman EJ, Jensen JH, Babb JS, et al. Cognitive im­pairment in mild traumatic brain injury: A longitudi­nal diffusional kurtosis and perfusion imaging study. Am J Neuroradiol 2013; 34(5): 951-957.

23. Newsome MR, Scheibel RS, Chu Z, et al. The relation­ship of resting cerebral blood flow and brain activa­tion during a social cognition task in adolescents with chronic moderate to severe traumatic brain injury: A preliminary investigation. Int J Dev Neurosci. 2012; 30 (3): 255-266.

24. Rempp KA, Brix G, Wenz F, et al. Quantification of re­gional cerebral blood flow and volume with dynamic susceptibility contrast-enhanced MR imaging. Radiol­ogy 1994; 193(3): 637-641.

25. Tofts PS. Modeling tracer kinetics in dynamic Gd-DT­PA MR imaging. J Magn Reson Imaging 1997; 7: 91-101.

26. Ostergaard L, Weisskoff RM, Chesler DA,et al. High resolution measurement of cerebral blood flow us­ing intravascular tracer bolus passages, part 1: Math­ematical approach and statistical analysis. Magn Re­son Med 1996; 36: 715-725.

27. Knutsson L, Stahlberg F, Wirestam R. Aspects on the accuracy of cerebral perfusion parameters obtained by dynamic susceptibility contrast MRI: A simulation study. Magn Reson Imaging 2004; 22: 789-798.

28. Garnett MR, Blamire AM, Corkill RG, et al. Abnormal cerebral blood volume in regions of contused and normal appearing brain following traumatic brain

injury using perfusion magnetic resonance imaging. J Neurotrauma 2001; 18(6): 585-593.

29. Kou Z, Ye Y, Haacke EM. Evaluating the Role of Re­duced Oxygen Saturation and Vascular Damage in Traumatic Brain Injury Using Magnetic Resonance Perfusion-Weighted Imaging and Susceptibili­ty-Weighted Imaging and Mapping. Top Magn Reson Imaging 2015; 24: 253-265.

30. Liu W, Wang B, Wolfowitz R, et al. Perfusion deficits in patients with mild traumatic brain injury charac­terized by dynamic susceptibility contrast MRI. NMR Biomed 2013; 26(6): 651-663.

31. Wiedmann KD, Wilson JT, Wyper D, et al. SPECT cer­ebral blood flow, MR imaging, and neuropsycholog­ical findings in traumatic head injury. Neuropsychol­ogy 1989; 3: 267-281.

32. Umile EM, Sandel ME, Alavi A, et al. Dynamic imag­ing in mild traumatic brain injury: Support for the theory of medial temporal vulnerability. Arch Phys Med Rehabil 2002; 83(11): 1506-1513.

33. Kato T, Nakayama N, Yasokawa Y, et al. Statistical image analysis of cerebral glucose metabolism in pa­tients with cognitive impairment following diffuse traumatic brain injury. J Neurotrauma 2007; 24(6): 919-926.

34. Hofman PA, Stapert SZ, van Kroonenburgh MJ, et al. MR imaging, single-photon emission CT, and neuro­cognitive performance after mild traumatic brain injury. Am J Neuroradiol 2001; 22(3): 441-449.

35. Jorge RE, Robinson RG, Starkstein SE, et al. Depres­sion and anxiety following traumatic brain injury. J Neuropsychiat 1993; 5: 369-374.

36. Mooney G, Speed J. The association between mild traumatic brain injury and psychiatric conditions. Brain Inj 2001; 15(10): 865-877.

37. Campbell S, Macqueen G. The role of the hippocam­pus in the pathophysiology of major depression. J Psychiatry Neurosci. 2004; 29(6): 417-426.

38. Koenigs M, Huey ED, Calamia M, et al. Distinct re­gions of prefrontal cortex mediate resistance and vulnerability to depression. J Neurosci 2008; 28(47): 12341-12348.

39. Rudebeck PH, Bannerman DM, Rushworth MF. The contribution of distinct subregions of the ventromedial frontal cortex to emotion, social behavior, and decision making. Cogn Affect Behav Neurosci. 2008; 8(4): 485-497.

40. Levin HS, Goldstein FC, MacKenzie EJ. Depression as a Secondary Condition Following Mild and Moder­ate Traumatic Brain Injury. Semin Clin Neuropsychia­try 1997; 2(3): 207-215.

41. Ruff RM, Camenzuli L, Mueller J. Miserable minor­ity: Emotional risk factors that influence the out­come of a mild traumatic brain injury. Brain Inj 1996; 10(8): 551-565.

42. Dikmen SS, Machamer JE, Winn HR, et al. Neuropsy­chological outcome at 1-year post head injury. Neu­ropsychology 1995; 9(1): 80-90.

43. Lannoo E, Colardyn F, Vandekerckhove T, et al. Sub­jective complaints versus neuropsychological test performance after moderate to severe head injury. Acta Neurochir Wien 1998; 140(3): 245-253.

44. Teasdale G, Jennett B. Assessment of coma and im­paired consciousness. A practical scale. Lancet 1974; 2(7872): 81-84.

45. Simos, P G, Papastefanakis E, Panou T, et al. The Greek memory scale. (2011) Rethymno: Laboratory of Applied Psychology, University of Crete

46. Simos P, Ktistaki G, Dimitraki G, et al. Cognitive defi­cits early in the course of rheumatoid arthritis. J Clin Exp Neuropsychol 2016; 38: 820-829.

47. Hubley AM, Tremblay D. Comparability of total score performance on the Rey- Osterrieth Complex Figure and a modified Taylor Complex Figure. J. Clin. Exp. Neuropsychol 2002; 24: 370-382.

48. Fountoulakis K, Iacovides A, Kleanthous S, et al. Re­liability, validity and psychometric properties of the Greek translation of the Center for Epidemio­logical Studies-Depression (CES-D) Scale. BMC Psy­chiatry. 2001; 1: 3.

49. Fountoulakis K, Papadopoulou M, Kleanthous S, et al. Reliability and psychometric properties of the Greek translation of the state-trait anxiety invento­ry form Y: Preliminary data. Ann Gen Psychiatry 2006; 31(5): 2.

50. Menon DK. Brain ischaemia after traumatic brain in­jury: lessons from 15O2 positron emission tomogra­phy. Curr. Opin. Crit Care 2006; 12: 85-89.

51. Rostami E, Engquist H, Enblad P. Imaging of cere­bral blood flow in patients with severe traumatic brain injury in the neurointensive care. Front Neu­rol. 2014; 5: 114.

52. Pasco A, Lemaire L, Franconi F, et al. Perfusional deficit and the dynamics of cerebral edemas in ex­perimental traumatic brain injury using perfusion and diffusion-weighted magnetic resonance imag­ing. J. Neurotrauma 2007; 24: 1321-1330.

53. Jacobs A, Put E, Ingels M, et al. One-year follow-up of technetium-99m-HMPAO SPECT in mild head in­jury. J Nucl Med 1996; 37: 1605-1609.

54. Abdel-Dayem HM, Abu-Judeh H, Kumar M, et al. SPECT brain perfusion abnormalities in mild or moderate traumatic brain injury. Clin. Nucl. Med. 1998; 23(5): 309-317.

55. Stamatakis EA, Wilson JT, Hadley DM, et al. SPECT imaging in head injury interpreted with statisti­cal parametric mapping. J. Nucl. Med. 2002; 43(4): 476-483.

56. Gross H, Kling A, Henry G, et al. Local cerebral glu­cose metabolism in patients with long-term behav­ioral and cognitive deficits following mild traumat­ic brain injury. J Neuropsychiatry Clin Neurosci. 1996; 8(3): 324-334.

57. Barkai G, Goshen E, Tzila ZS, et al. Acetazolamide-en­hanced neuro SPECT scan reveals functional impair­ment after minimal traumatic brain injury not oth­erwise discernible. Psychiatry Res. 2004; 132: 279-283.

58. Lewine JD, Davis JT, Bigler ED, et al. Objective docu­mentation of traumatic brain injury subsequent to mild head trauma: Multimodal brain imaging with MEG, SPECT, and MRI. J. Head Trauma Rehabil. 2007; 22: 141-155.

59. Bonne O, Gilboa A, LouzounY, et al. Cerebral blood flow in chronic symptomatic mild traumatic brain injury. Psychiatry Res 2003; 124: 141-152.

60. Kinuya K, Kakuda K, Nobata K, et al. Role of brain perfusion single-photon emission tomography in traumatic head injury. Nucl Med Commun 2004; 25(4): 333-337.

61. Peskind ER, Petrie EC, Cross DJ, et al. Cerebrocerebel­lar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent postconcussive symptoms. Neuroimage 2011; 54(Suppl 1): S76-82.

62. Nakayama N, Okumura A, Shinoda J, et al. Relation­ship between regional cerebral metabolism and con­sciousness disturbance in traumatic diffuse brain in­jury without large focal lesions: An FDGPET study with statistical parametric mapping analysis. J Neu­rol Neurosurg Psychiatry 2006; 77: 856-862.

63. Haacke WR, Wu B, Kou Z. The presence of venous damage and microbleeds in traumatic brain injury and the potential future role of angiographic and perfusion magnetic resonance imaging. In: Christian W, Kreipke JAR, eds. 2013. Cerebral Blood Flow, Me­tabolism, Head Trauma.

64. Varney NR, Bushnell DL, Nathan M, et al. NeuroS­PECT correlates of disabling mild head injury: Pre­liminary findings. J Head Trauma Rehabil 1995;10 (3): 18-28.

65. Rao N, Turski PA, Polcyn RE, et al. 18F positron emis­sion computed tomography in closed head injury. Arch Phys Med Rehabil 1984; 65: 780-785.

66. Nakashima T, Nakayama N, Miwa K, et al. Focal brain glucose hypometabolism in patients with neuropsy­chologic deficits after diffuse axonal injury. Am. J. Neuroradiol 2007; 28(2): 236-242.

67. Raji CA, Tarzwell R, Pavel D, et al. Clinical utility of SPECT neuroimaging in the diagnosis and treatment of traumatic brain injury: A systematic review. PLoS ONE 20149, e91088.

68. Papadaki EZ, Mastorodemos VC, Amanakis EZ, et al. White matter and deep gray matter hemodynamic changes in multiple sclerosis patients with clinical­ly isolated syndrome. Magn Reson Med. 2012; 68(6): 1932-1942.

69. Bigler ED, Blatter DD, Anderson CV, et al. Hippocam­pal volume in normal aging and traumatic brain in­jury. Am J Neuroradiol 1997; 18(1): 11-23.

70. Himanen L, Portin R, Isoniemi H, et al. Cognitive functions in relation to MRI findings 30 years after traumatic brain injury. Brain Inj. 2005; 19(2): 93-100.

71. Broshek DK, De Marco AP, Freeman JR. A review of post-concussion syndrome and psychological fac­tors associated with concussion. Brain Inj. 2015; 29(2): 228-237.

72. Perry DC, Sturm VE, Peterson MJ, et al. Association of traumatic brain injury with subsequent neurolog­ical and psychiatric disease: A meta-analysis. J Neu­rosurg 2016; 124(2): 511-526.

73. Wang SH, Morris RG. Hippocampal-neocortical in­teractions in memory formation, consolidation, and reconsolidation. Annu Rev Psychol 2010; 61:49- 79, C1-4.

74. Ritchey M, Libby LA, Ranganath C. Cortico-hip­pocampal systems involved in memory and cogni­tion: The PMAT framework. Prog Brain Res. 2015; 219: 45-64.

75. Campbell S, Macqueen G. The role of the hippocam­pus in the pathophysiology of major depression. J Psychiatry Neurosci 2004; 29(6): 417-426.

76. Köhler S, van Boxtel MP, van Os J, et al. Depres­sive symptoms and cognitive decline in communi­ty-dwelling older adults. J Am Geriatr Soc 2010; 58 (5): 873-879.

77. Panza F, D’Introno A, Colacicco AM, et al. Temporal relationship between depressive symptoms and cog­nitive impairment: The Italian Longitudinal Study on Aging. J Alzheimers Dis 2009; 17(4): 899-911.

78. Suzuki H, Matsumoto Y, Ota H, et al. Hippocampal Blood Flow Abnormality Associated With Depressive Symptoms and Cognitive Impairment in Patients With Chronic Heart Failure. Circ J 2016.

79. Knutson KM, Rakowsky ST, Solomon J, et al. Injured brain regions associated with anxiety in Vietnam veterans. Neuropsychologia 2013; 51(4): 686-694.

80. Davidson RJ, Lewis DA, Alloy LB, et al. Neural and be­havioral substrates of mood and mood regulation. Biol Psychiatry 2002; 52(6): 478-502.

81. Bishop, S.J. Neurocognitive mechanisms of anxiety: An integrative account. Trends in Cognitive Sciences 2007; 11, 307-316.

82. Belanger HG, Curtiss G, Demery JA, et al. Factors moderating neuropsychological outcomes follow­ing mild traumatic brain injury: A meta-analysis. J Int Neuropsychol Soc 2005; 11(3): 215-227.

83. Langeluddecke PM, Lucas SK. WMS-III findings in lit­igants following moderate to extremely severe brain trauma. J Clin Exp Neuropsychol 2005; 27(5): 576-590.

84. Covassin T, Bay E. Are there gender differences in cognitive function, chronic stress, and neurobehav­ioral symptoms after mild-to-moderate traumatic brain injury? J Neurosci Nurs 2012; 44(3): 124-133.

85. Faust K, Nelson BD, Sarapas C, et al. Depression and performance on the repeatable battery for the as­sessment of neuropsychological status. Appl Neu­ropsychol Adult 2016; 7: 1-7.

86. Johnson LA, Mauer C, Jahn D, et al. Cognitive differ­ences among depressed and non-depressed MCI par­ticipants: A project FRONTIER study. Int J Geriatr Psy­chiatry 2013; 28(4): 377-382.

87. Yoo I, Woo JM, Lee SH, et al. Influence of anxiety symptoms on improvement of neurocognitive func­tions in patients with major depressive disorder: A 12-week, multicenter, randomized trial of tianeptine versus escitalopram, the CAMPION study. J Affect Dis­ord 2015; 185: 24-30.

88. Avila R, Ribeiz S, Duran FL, et al. Effect of tempo­ral lobe structure volume on memory in elder­ly depressed patients. Neurobiol Aging 2011; 32(10): 1857-1867.

89. McGehee BE, Pollock JM, Maldjian JA. Brain perfu­sion imaging: How does it work and what should I use? J Magn Reson Imaging 2012; 36: 1257-1272.

90. Detre JA, Zhang W, Roberts DA, et al. Tissue specific perfusion imaging using arterial spin labeling. NMR Biomed 1994; 7: 75-78.



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