TY - JOUR
AU - Sharp, David, J
AB - Abstract Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal dopamine abnormalities using 123I-Ioflupane single-photon emission computed tomography (SPECT) scans and their relationship to nigrostriatal damage and clinical features. We studied 42 moderate–severe traumatic brain injury patients with cognitive impairments but no motor parkinsonism signs and 20 healthy controls. 123I-Ioflupane scanning was used to assess dopamine transporter levels. Clinical scan reports were compared to quantitative dopamine transporter results. Advanced MRI methods were used to assess the nigrostriatal system, including the area through which the nigrostriatal projections pass as defined from high-resolution Human Connectome data. Detailed clinical and neuropsychological assessments were performed. Around 20% of our moderate–severe patients had clear evidence of reduced specific binding ratios for the dopamine transporter in the striatum measured using 123I-Ioflupane SPECT. The caudate was affected more consistently than other striatal regions. Dopamine transporter abnormalities were associated with reduced substantia nigra volume. In addition, diffusion MRI provided evidence of damage to the regions through which the nigrostriatal tract passes, particularly the area traversed by dopaminergic projections to the caudate. Only a small percentage of patients had evidence of macroscopic lesions in the striatum and there was no relationship between presence of lesions and dopamine transporter specific binding ratio abnormalities. There was also no relationship between reduced volume in the striatal subregions and reduced dopamine transporter specific binding ratios. Patients with low caudate dopamine transporter specific binding ratios show impaired processing speed and executive dysfunction compared to patients with normal levels. Taken together, our results suggest that the dopaminergic system is affected by a moderate–severe traumatic brain injury in a significant proportion of patients, even in the absence of clinical motor parkinsonism. Reduced dopamine transporter levels are most commonly seen in the caudate and this is likely to reflect the pattern of nigrostriatal tract damage produced by axonal injury and associated midbrain damage. traumatic brain injury, dopamine, cognitive impairment, SPECT imaging, ioflupane Introduction Traumatic brain injury (TBI) can damage the dopaminergic system. Animal models of TBI show both dopaminergic cell loss (van Bregt et al., 2012) and biochemical disturbance of the dopaminergic system. Biochemically, a brief transitory rise in dopamine levels throughout the brain (Huger and Patrick, 1979; McIntosh et al., 1994; Massucci et al., 2004; Kobori et al., 2006) is followed by a functional hypodopaminergic state (Wagner et al., 2005b). Human neuropathology studies also show head injuries cause gross and microscopic changes to the substantia nigra (Smith et al., 2013). The dopaminergic cell bodies reside in two main nuclei in the midbrain, the substantia nigra and the ventral tegmental area (Bjorklund and Dunnett, 2007). These nuclei are therefore susceptible to midbrain and brainstem injuries that are common after TBI, particularly in those patients with poor outcome (Adams et al., 1989). The ascending dopaminergic neurons project to subcortical and cortical areas, with striatal projections travelling through the nigrostriatal tract. These ascending fibres are likely to be susceptible to damage from shearing forces generated by trauma, but this has not previously been investigated. Computational models show high strain across the midbrain when subjected to external forces as the brain pivots in this region, thereby providing a biomechanical explanation for susceptibility to injury in this area (Zhang et al., 2001). Striatal dopamine abnormalities can be assessed in vivo using single-photon emission computed tomography (SPECT) imaging to measure dopamine transporter (DaT) expression (Yan et al., 2002; Wagner et al., 2005a, 2009; Wilson et al., 2005). This imaging technique is widely used in the diagnosis of Parkinson’s disease (Marek et al., 1996; Wenning et al., 1998; Benamer et al., 2003). DaT is located on presynaptic dopaminergic neurons [Fig. 1A(ii)] with extracellular dopamine levels and neural activity regulating its expression (Gulley and Zahniser, 2003). DaT levels are reduced secondary to dopaminergic cell loss or to a compensatory downregulation because of reduced dopamine levels. In humans, two small imaging studies have shown reduced overall striatal DaT binding using SPECT and PET after TBI (Donnemiller et al., 2000; Wagner et al., 2014). Figure 1 Open in new tabDownload slide Methods. [A(i)] 123I-Ioflupane SPECT scan analysis: individual reconstructed 123I-Ioflupane SPECT scans were co-registered with their native T1 MRI using rigid transformation. T1 images were warped to an average group template using a diffeomorphic non-linear registration (DARTEL). Templates were registered to Montreal Neurological Institute 152 (MNI) space. Then the individual flow-fields and template transformation from DARTEL were applied to the SPECT images to produce MNI space images, without modulation. (ii) Schematic of a dopaminergic synapse illustrating the role of the presynaptic DaT in reuptaking synaptic dopamine: DA = dopamine; DOPA = l-3,4-dihydroxyphenylalanine; L-AAD = l-amino acid decarboxylase; nvDA = non-vesicular dopamine; VMAT2 = vesicular monoamine transporter 2. (B) Volumetric MRI analysis: T1 images were warped to MNI space (as above) but including modulation by the Jacobian determinants derived from DARTEL. A mask of the substantia nigra and striatum in standard space were used to calculate volumes for these structures in each individual. (C) Diffusion MRI analysis: (i) Making the nigrostriatal mask. Fibre-tracking using the MRtrix package was performed on 100 subjects from the Human Connectome Project (HCP) to create binarized masks for the nigro-striatal tract as a whole, as well as the subregions; nigro-caudate, nigro-putamen and nigro-nucleus accumbens tracts. (ii) Processing diffusion data: diffusion-weighted images were preprocessed using standard methods and tensor-based registration performed using DTI-TK. Figure 1 Open in new tabDownload slide Methods. [A(i)] 123I-Ioflupane SPECT scan analysis: individual reconstructed 123I-Ioflupane SPECT scans were co-registered with their native T1 MRI using rigid transformation. T1 images were warped to an average group template using a diffeomorphic non-linear registration (DARTEL). Templates were registered to Montreal Neurological Institute 152 (MNI) space. Then the individual flow-fields and template transformation from DARTEL were applied to the SPECT images to produce MNI space images, without modulation. (ii) Schematic of a dopaminergic synapse illustrating the role of the presynaptic DaT in reuptaking synaptic dopamine: DA = dopamine; DOPA = l-3,4-dihydroxyphenylalanine; L-AAD = l-amino acid decarboxylase; nvDA = non-vesicular dopamine; VMAT2 = vesicular monoamine transporter 2. (B) Volumetric MRI analysis: T1 images were warped to MNI space (as above) but including modulation by the Jacobian determinants derived from DARTEL. A mask of the substantia nigra and striatum in standard space were used to calculate volumes for these structures in each individual. (C) Diffusion MRI analysis: (i) Making the nigrostriatal mask. Fibre-tracking using the MRtrix package was performed on 100 subjects from the Human Connectome Project (HCP) to create binarized masks for the nigro-striatal tract as a whole, as well as the subregions; nigro-caudate, nigro-putamen and nigro-nucleus accumbens tracts. (ii) Processing diffusion data: diffusion-weighted images were preprocessed using standard methods and tensor-based registration performed using DTI-TK. The striatum is subdivided into the caudate, putamen and nucleus accumbens, which have distinct functions. In Parkinson’s disease, motor abnormalities are associated with early DaT reductions in the posterior putamen (Guttman et al., 1997; Ma et al., 2002). As abnormalities progress anteriorly to involve the caudate, patients show more cognitive impairment (Ekman et al., 2012). Following a single TBI patients rarely show motor parkinsonism features (Krauss and Jankovic, 2002), but commonly show cognitive impairments that overlap with those seen in Parkinson’s disease (Kehagia et al., 2010). This could be explained by a non-uniform pattern of DaT abnormalities within the striatum. Here we extend this previous work in a large study using a multi-modal imaging approach to explore the location of dopaminergic abnormalities within the striatum and its relation to structural damage within the nigrostriatal system. 123I-Ioflupane SPECT was used to calculate DaT-specific binding ratios (SBRs) within the striatum. Advanced diffusion and volumetric MRI methods were used to investigate post-traumatic damage to the substantia nigra and ascending nigrostriatal fibres defined using high resolution Human Connectome Project data (Van Essen et al., 2013). The following hypotheses were tested: (i) DaT levels are reduced following moderate-to-severe TBI; (ii) DaT levels in areas of the striatum related to cognitive functioning (caudate) are affected more than areas associated with motor functioning (putamen); (iii) evidence of structural damage to the substantia nigra and/or the areas through which the ascending nigrostriatal fibres pass relate to reduced striatal DaT levels; and (iv) alterations in striatal DaT levels relate to cognitive impairments; in particular, processing speed, attention and executive functions. Materials and methods The study was approved by the West London and GTAC NRES Committee (14/LO/0067). All participants provided informed consent. Eligibility, groups and screening Patients were recruited from specialist TBI clinics in London, UK. Inclusion criteria were: (i) aged 20–65 years; (ii) history of single moderate–severe TBI (Mayo classification; Malec et al., 2007) at least 3 months prior; and (iii) subjective complaint of cognitive difficulties by participant, treating clinician, or caregiver. Exclusion criteria included: (i) neurological or psychiatric illness diagnosed prior to TBI; (ii) drug or alcohol addiction; (iii) positive urine drug screen; (iv) contraindication to MRI or SPECT; (v) contraindication to methylphenidate use (as this study formed part of a clinical trial, which will be reported separately); or (vi) clinical evidence of motor signs of parkinsonism as assessed by a neurologist. Following baseline neuropsychological assessment, SPECT and MRI scans; the TBI patients were randomized into a double-blind placebo-controlled cross-over study of methylphenidate, which is the subject of a separate publication (in preparation). A group of 20 age-matched, healthy control participants were used for the SPECT and MRI analyses. They were in good general health with no history of significant illness, and ineligible if they met any exclusion criteria above. A screening visit involved medical history and physical examination including the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale (Goetz et al., 2007). None of the patients screened had evidence of motor parkinsonism. Study design A cross-sectional study of 42 TBI patients compared to 20 controls was performed. All participants had 123I-Ioflupane SPECT, MRI including volumetric T1 and diffusion MRI, and detailed neuropsychological testing. Study procedures Study procedures were carried out at the Hammersmith Hospital, Imperial College London (London, UK) and Charing Cross Hospital (London, UK). 123I-Ioflupane SPECT Before administration of 123I-Ioflupane, patients received potassium iodide tablets (2 × 60 mg) to minimize radiation exposure to the thyroid gland. One hour later, a bolus intravenous injection of 123I-Ioflupane (GE Healthcare Ltd) was administered to each individual (mean activity 185 MBq). SPECT images for all subjects were acquired using the same dual-headed gamma camera (Symbia T16, Siemens Healthcare) at 180 min post-injection with LEHR collimators, 128 × 128 matrix, 1.45 zoom, 128 projections, and 30 s per projection. MRI All participants had a T1-weighted high resolution MPRAGE scan (160 1-mm thick transverse slices, repetition time = 2300 ms, echo time = 2.98 ms, flip angle = 9°, in-plane resolution = 1 × 1 mm, matrix size = 256 × 256, field of view = 25.6 × 25.6 cm). Diffusion-weighted images were acquired along 64 non-colinear directions with b = 1000 s/mm2 and four averages with b = 0 s/mm2, with echo time/repetition time 103/9500 ms, 64 contiguous slices, field of view 256 mm, and voxel size 2 mm3. Neuropsychological assessment A previously described neuropsychological battery assessed cognitive domains often observed to be impaired after TBI (Kinnunen et al., 2011) (Table 1). In addition, questionnaires were used to assess apathy (the Lille Apathy Rating Scale; Sockeel et al., 2006), fatigue (the Visual Analogue Scale of Fatigue; Lee et al., 1991), and changes in behaviour post-injury (both the ‘self’ and ‘family’ versions of the Frontal Systems Behaviour Scale; Grace and Malloy, 2001). Functional outcome was assessed in patients using the Glasgow Outcome Scale-Extended (GOS-E) (Wilson et al., 1998) (Supplementary Table 2). Table 1 Neuropsychological measures in healthy controls and patients with traumatic brain injury Cognitive domain Neuropsychological test Controls Patients W P Mean (±SD) Mean (±SD) n = 20 n = 42 Processing Speed Trail Making Test A (s) 19.4 (5.9) 30.5 (16.0) 214.5 0.003 Trail Making Test B (s) 45.3 (26.6) 66.4 (29.5) 197 0.001 Stroop Color Naming and Word Reading Composite Score (s) 25.2 (5.9) 31.1 (7.6) 210 0.001 CRT median RT (ms) 378 (60) 421 (54) 216 0.03 CRT RT SD (ms) 69 (24) 86 (33) 221.5 0.03 Executive Function Trail Making Test B − A (s) 25.9 (22.7) 35.9 (20.9) 255.5 0.02 Stroop Inhibition (s) 50.9 (12.6) 60.9 (15.2) 250 0.01 Stroop Inhibition-Switching (s) 56.4 (15.7) 72.2 (18.0) 188 <0.001 Stroop Inhibition-Switching versus baseline contrast (s) 31.6 (12.0) 41.5 (13.0) 226 0.003 Memory PT Immediate Recall 31.2 (3.9) 22.7 (7.3) 698 <0.001 PT Delayed Recall 10.8 (2.3) 8.1 (3.4) 588.5 0.002 PT Forgetting 1.1 (2.3) 2.0 (2.2) 275 0.04 Intellectual Ability WTAR Scaled 117.5 (5.5) 107.0 (11.5) 672 <0.001 WASI Matrix Reasoning 28.6 (4.6) 27.5 (4.5) 473 0.43 Cognitive domain Neuropsychological test Controls Patients W P Mean (±SD) Mean (±SD) n = 20 n = 42 Processing Speed Trail Making Test A (s) 19.4 (5.9) 30.5 (16.0) 214.5 0.003 Trail Making Test B (s) 45.3 (26.6) 66.4 (29.5) 197 0.001 Stroop Color Naming and Word Reading Composite Score (s) 25.2 (5.9) 31.1 (7.6) 210 0.001 CRT median RT (ms) 378 (60) 421 (54) 216 0.03 CRT RT SD (ms) 69 (24) 86 (33) 221.5 0.03 Executive Function Trail Making Test B − A (s) 25.9 (22.7) 35.9 (20.9) 255.5 0.02 Stroop Inhibition (s) 50.9 (12.6) 60.9 (15.2) 250 0.01 Stroop Inhibition-Switching (s) 56.4 (15.7) 72.2 (18.0) 188 <0.001 Stroop Inhibition-Switching versus baseline contrast (s) 31.6 (12.0) 41.5 (13.0) 226 0.003 Memory PT Immediate Recall 31.2 (3.9) 22.7 (7.3) 698 <0.001 PT Delayed Recall 10.8 (2.3) 8.1 (3.4) 588.5 0.002 PT Forgetting 1.1 (2.3) 2.0 (2.2) 275 0.04 Intellectual Ability WTAR Scaled 117.5 (5.5) 107.0 (11.5) 672 <0.001 WASI Matrix Reasoning 28.6 (4.6) 27.5 (4.5) 473 0.43 Independent Sample t-tests were conducted using the Wilcoxon Rank Sum Test. All significant tests <0.05 survive multiple comparison correction using the FDR method. CRT = choice reaction time; PT = People’s Test; RT = reaction time; WASI = Wechsler Abbreviated Scale for Intelligence; WTAR = Wechsler Test of Adult Reading. Table 1 Neuropsychological measures in healthy controls and patients with traumatic brain injury Cognitive domain Neuropsychological test Controls Patients W P Mean (±SD) Mean (±SD) n = 20 n = 42 Processing Speed Trail Making Test A (s) 19.4 (5.9) 30.5 (16.0) 214.5 0.003 Trail Making Test B (s) 45.3 (26.6) 66.4 (29.5) 197 0.001 Stroop Color Naming and Word Reading Composite Score (s) 25.2 (5.9) 31.1 (7.6) 210 0.001 CRT median RT (ms) 378 (60) 421 (54) 216 0.03 CRT RT SD (ms) 69 (24) 86 (33) 221.5 0.03 Executive Function Trail Making Test B − A (s) 25.9 (22.7) 35.9 (20.9) 255.5 0.02 Stroop Inhibition (s) 50.9 (12.6) 60.9 (15.2) 250 0.01 Stroop Inhibition-Switching (s) 56.4 (15.7) 72.2 (18.0) 188 <0.001 Stroop Inhibition-Switching versus baseline contrast (s) 31.6 (12.0) 41.5 (13.0) 226 0.003 Memory PT Immediate Recall 31.2 (3.9) 22.7 (7.3) 698 <0.001 PT Delayed Recall 10.8 (2.3) 8.1 (3.4) 588.5 0.002 PT Forgetting 1.1 (2.3) 2.0 (2.2) 275 0.04 Intellectual Ability WTAR Scaled 117.5 (5.5) 107.0 (11.5) 672 <0.001 WASI Matrix Reasoning 28.6 (4.6) 27.5 (4.5) 473 0.43 Cognitive domain Neuropsychological test Controls Patients W P Mean (±SD) Mean (±SD) n = 20 n = 42 Processing Speed Trail Making Test A (s) 19.4 (5.9) 30.5 (16.0) 214.5 0.003 Trail Making Test B (s) 45.3 (26.6) 66.4 (29.5) 197 0.001 Stroop Color Naming and Word Reading Composite Score (s) 25.2 (5.9) 31.1 (7.6) 210 0.001 CRT median RT (ms) 378 (60) 421 (54) 216 0.03 CRT RT SD (ms) 69 (24) 86 (33) 221.5 0.03 Executive Function Trail Making Test B − A (s) 25.9 (22.7) 35.9 (20.9) 255.5 0.02 Stroop Inhibition (s) 50.9 (12.6) 60.9 (15.2) 250 0.01 Stroop Inhibition-Switching (s) 56.4 (15.7) 72.2 (18.0) 188 <0.001 Stroop Inhibition-Switching versus baseline contrast (s) 31.6 (12.0) 41.5 (13.0) 226 0.003 Memory PT Immediate Recall 31.2 (3.9) 22.7 (7.3) 698 <0.001 PT Delayed Recall 10.8 (2.3) 8.1 (3.4) 588.5 0.002 PT Forgetting 1.1 (2.3) 2.0 (2.2) 275 0.04 Intellectual Ability WTAR Scaled 117.5 (5.5) 107.0 (11.5) 672 <0.001 WASI Matrix Reasoning 28.6 (4.6) 27.5 (4.5) 473 0.43 Independent Sample t-tests were conducted using the Wilcoxon Rank Sum Test. All significant tests <0.05 survive multiple comparison correction using the FDR method. CRT = choice reaction time; PT = People’s Test; RT = reaction time; WASI = Wechsler Abbreviated Scale for Intelligence; WTAR = Wechsler Test of Adult Reading. Image analysis 123I-Ioflupane SPECT Acquired data were reconstructed with an Ordered Subsets Expectation–Maximization (OSEM)-based iterative algorithm (HybridRecon, HERMES Medical Solutions; Stockholm, Sweden) including corrections for attenuation, scatter, and resolution [Fig. 1A(i)]. The reconstructed SPECT images were co-registered with their corresponding native T1 MRI image. T1 images were segmented into grey and white matter using SPM12, and warped to an average group template using a diffeomorphic non-linear registration (DARTEL) (Ashburner, 2007). Templates were registered to Montreal Neurological Institute 152 (MNI) space. Then the individual flow-fields and template transformation from DARTEL were applied to the SPECT images to produce MNI space images, without modulation. The SBR was calculated for the whole striatum and the caudate, putamen and nucleus accumbens separately. The SBR was calculated using the formula [(region of interest counts − background counts)/background counts] where the background counts were calculated from the occipital cortex, an area of low DaT expression. The SBR is a semi-quantitative technique that takes into account variations in non-specific uptake of 123I-Ioflupane between individuals. It makes the assumption that the non-specific uptake is equivalent throughout the brain. All SPECT images were also independently reported by two nuclear medicine consultants following a predefined ranking scale of normal, abnormal or indeterminate. Any discrepancies between reports were resolved by consensus opinion to give a single result per scan. Lesion segmentation In patients, lesions apparent on T1 MRI were manually segmented and excluded from all imaging analyses (Fig. 2). In addition, lesion volumes within the striatum and frontal lobe were measured to test for a relationship between the presence and size of lesions and striatal SBR. Figure 2 Open in new tabDownload slide Lesion map. Thirty patients had focal lesions visible on T1 MRI. These were overlaid to produce a lesion map. Maximal areas of overlap of lesions were seen in the anterior frontal and temporal lobes. There were no lesions in the substantia nigra (light blue) and minimal lesion load in the striatum (green) and in the area through which the nigrostriatal tract passes (dark blue). Figure 2 Open in new tabDownload slide Lesion map. Thirty patients had focal lesions visible on T1 MRI. These were overlaid to produce a lesion map. Maximal areas of overlap of lesions were seen in the anterior frontal and temporal lobes. There were no lesions in the substantia nigra (light blue) and minimal lesion load in the striatum (green) and in the area through which the nigrostriatal tract passes (dark blue). Voxel-based morphometry For cross-sectional voxel-based morphometry, T1 images were segmented into grey and white matter, and warped to MNI space (as above) but including modulation by the Jacobian determinants (JDs) derived from DARTEL (Fig. 1B). The normalized segmentations were then smoothed (4 mm full-width at half-maximum) and masked (group mean P > 0.2). Total grey and white matter tissue volumes, and intracranial volume (ICV), were calculated using SPM12. A mask of the substantia nigra (Keuken et al., 2014) and striatum (derived from the Harvard-Oxford probabilistic anatomical atlas within FSL) in MNI space were thresholded at >50% probability and used to calculate volumes for these structures in each individual by overlaying on the individual normalized volumetric images. Diffusion tensor imaging Diffusion-weighted images were preprocessed using standard methods (Kinnunen et al., 2011) and tensor-based registration performed using DTI-TK (Zhang et al., 2007) (Fig. 1C). Maps of fractional anisotropy and mean diffusivity were generated from MNI space tensor images. A map of the area through which the nigrostriatal tract passes, as well as nigro-caudate, nigro-putamen and nigro-nucleus accumbens components of this tract, was created using 100 subjects from the Human Connectome Project (Van Essen et al., 2013). Fibre-tracking was performed in both directions between the left and right substantia nigra and the corresponding nucleus accumbens, putamen and caudate using the MRtrix package (Tournier et al., 2012). Three thousand tracks were performed with maximum angle between successive steps limited to 45°. A probability mask based on the percentage of tracks passing through each voxel was created for each individual and thresholded at 5%. All masks were binarized and masks from the two directions of tracking were combined. A group probabilistic mask that was then thresholded at 25% to create a group mask. Statistical analyses Group characteristics were compared using independent sample t-tests (for age) and Fisher’s exact test (gender). Voxelwise cross-sectional comparison of 123I-Ioflupane SBR was performed using non-parametric permutation tests (Nichols and Holmes, 2002) in FSL (5000 permutations). Age was added as a nuisance covariate. All results were cluster corrected using threshold-free cluster enhancement (Smith and Nichols, 2009) with family-wise error rate of P < 0.05. For the 123I-Ioflupane SBR region of interest analysis, a linear mixed-effects model was used to assess group differences within the subdivisions of the striatum (caudate, putamen and nucleus accumbens). Group and region of interest were defined as fixed effects, whereas subject was defined as a random effect to model variability in subject intercepts. Age was included as a covariate. Post hoc unpaired sample t-tests were used to investigate any significant main effects or interactions. To remove the variance in SBR that relates to age from these post hoc tests, residuals from a linear regression of age on region SBR were used, then differences between patients and controls were assessed per region: caudate, putamen and nucleus accumbens. A similar linear mixed-effects model was used for analysis of diffusion metrics using multiple regions of interest (nigro-caudate, nigro-putamen and nigro-nucleus accumbens tracts). Age was included as a covariate. For volumetric analysis, volumes were corrected for total intracranial volume to remove differences caused by head size, and age was added as a nuisance covariate. Substantia nigra volumes were compared using an unpaired sample t-test. To assess the subdivisions of the striatum a mixed-effects model was used followed by post hoc unpaired sample t-tests. To explore the relationship between the structural measures (substantia nigra volume and tract diffusivity measures) and 123I-Ioflupane SBR we used linear regression to predict striatal subregion SBR with the structural measure and group (i.e. patient or control) as explanatory variables and age (and intracranial volume for volumetric measures) as nuisance variables. Differences in performance on neuropsychological tests and questionnaires for patients and controls were investigated with the use of Wilcoxon Rank Sum Tests for independent samples and corrected for multiple comparisons using the false discovery rate method. Subjects greater than 3 standard deviations (SD) from the mean on tests were considered outliers and removed from further analysis. This applied to four subjects in the Choice Reaction Task (one control removed for prolonged reaction time, two patients for excessive misses and one patient for excessive errors), one control in the People’s Test and two patients in the Trail Making Task. One control and one patient were also removed from the Choice Reaction Task analysis due to faulty equipment on the day of testing. To explore the relationship between neuropsychological performance and 123I-Ioflupane SBR, patients were split based on their clinical 123I-Ioflupane scan report and also based on the quantitative analysis using both 1 SD and 2 SD below the control mean for caudate, putamen, nucleus accumbens and whole striatum. Statistical analysis and graph illustration were performed using R version 3.3.2 (http://www.R-project.org/). Results Baseline characteristics Forty-two TBI patients and 20 healthy controls were enrolled. Patients comprised 36 males (86%) with mean age 39.8 years (SD 11.7, range 20–65). Median time since injury was 34 months (range 6–366 months) (Supplementary Table 1). There was no significant age difference with the healthy controls [16 males (80%), mean age ± SD 40.2 ± 12.9, range 21–61]. Thirty patients had one or more focal lesions (Fig. 2). The majority of lesions appeared in frontal and/or temporal lobes. No patients had focal lesions in the substantia nigra. Six patients had lesions involving the striatum. These lesions were all very small with the largest lesion load for a single patient comprising just 5% of the total striatal volume (range 0.8–5.0%, mean 3.1%). Lesioned areas were masked out of further analyses. Clinical reports of 123I-Ioflupane scans A third of patients (14/42) had abnormal 123I-Ioflupane scans on clinical reporting (Figs 3 and 4). No controls had scans reported as abnormal on clinical classification. Three controls and three patients were clinically classified as indeterminate. The pattern of loss of uptake was most often described as patchy. At the individual level, abnormalities were sometimes apparent throughout the striatum including the putamen and caudate, although these were often inconsistent across individuals. Figure 3 Open in new tabDownload slide 123I-Ioflupane SPECT scan examples. A selection of 16 TBI patients and three control subjects. Subject’s age, gender (M/F) and the time since injury in months is shown. The colour scale shows the 123I-Ioflupane SBR. Figure 3 Open in new tabDownload slide 123I-Ioflupane SPECT scan examples. A selection of 16 TBI patients and three control subjects. Subject’s age, gender (M/F) and the time since injury in months is shown. The colour scale shows the 123I-Ioflupane SBR. Figure 4 Open in new tabDownload slide Clinical 123I-Ioflupane SPECT scan reports and quantitative comparison. Comparison between individual clinical reporting and quantitative assessment of 123I-Ioflupane SPECT scans: each line represents a single subject. Red signifies ‘abnormal’ and blue ‘normal’. For the quantitative assessment in the whole striatum, caudate and putamen two criteria were used; >1 and >2 SD below the mean SBR in the control group. Figure 4 Open in new tabDownload slide Clinical 123I-Ioflupane SPECT scan reports and quantitative comparison. Comparison between individual clinical reporting and quantitative assessment of 123I-Ioflupane SPECT scans: each line represents a single subject. Red signifies ‘abnormal’ and blue ‘normal’. For the quantitative assessment in the whole striatum, caudate and putamen two criteria were used; >1 and >2 SD below the mean SBR in the control group. Patients show reduced 123I-Ioflupane specific binding ratios in the caudate Across the whole group, whole-brain voxelwise analysis showed patients had significantly lower SBR in the anterior striatum, with significant differences found exclusively in the caudate (Fig. 5A and B). SBR was not reduced in the putamen across the group. We then used a region of interest approach to explore the effect of TBI on striatal subregions (Fig. 5C). A mixed-effects model including the caudate, putamen and nucleus accumbens showed a region of interest x group interaction [F(2,120) = 3.08, P = 0.0495]. This was driven by a significantly lower SBR in the caudate for patients compared to controls [t(40.5) = −3.48, P = 0.001], with a difference that approached significance in the putamen (P = 0.052) and no difference in the nucleus accumbens (P = 0.236). The effect size for differences in caudate SBR was large (Cohen’s d = 0.92, 95% CI 0.35, to 1.49), but small in the putamen (Cohen’s d = 0.50, 95% CI −0.05 to 1.05) and nucleus accumbens (Cohen’s d = 0.32, 95% CI −0.23 to 0.86). Figure 5 Open in new tabDownload slide 123I-Ioflupane SPECT scan results. (A) Results of the voxelwise analysis: areas of significant reduction of 123I-Ioflupane SBR are shown in red/yellow. The striatal mask is shown for comparison in blue. The colour bar shows the corrected P-values. (B) Anatomical location of the caudate, putamen and nucleus accumbens for reference. (C) Region of interest analyses. Plots show 123I-Ioflupane SBR corrected for age for patients and controls in the caudate, putamen and nucleus accumbens. The SBR corrected for age are the residuals from the linear regression of age on SBR. **P = 0.001. Figure 5 Open in new tabDownload slide 123I-Ioflupane SPECT scan results. (A) Results of the voxelwise analysis: areas of significant reduction of 123I-Ioflupane SBR are shown in red/yellow. The striatal mask is shown for comparison in blue. The colour bar shows the corrected P-values. (B) Anatomical location of the caudate, putamen and nucleus accumbens for reference. (C) Region of interest analyses. Plots show 123I-Ioflupane SBR corrected for age for patients and controls in the caudate, putamen and nucleus accumbens. The SBR corrected for age are the residuals from the linear regression of age on SBR. **P = 0.001. Classifying individual patients 123I-Ioflupane scans Clinical classification was compared with quantitative results (Fig. 4). To allow comparison between the two sets of results scans clinically classified as ‘indeterminate’ were grouped with ‘normal’ scans. In addition, we categorized patients on quantitative results into normal and abnormal using two criteria; (i) >1 SD below the mean SBR in the control group; and (ii) >2 SD below the mean SBR. The more stringent criteria (2 SD) gave consistent results to the clinical classification with no false-positives in the control population. Using this approach, eight patients were classified as abnormal based on striatal SBR and seven based on caudate or putamen SBR. All these patients were also classified as abnormal on clinical assessment. The less stringent criterion (1 SD) led to three false positives in the controls and as expected more patients classified as abnormal (16 in the striatum, 18 in the caudate and 15 in the putamen). Classification based on the whole striatum (2 SD) showed the greatest concordance with the clinical classification (Cohen’s Kappa = 0.67). Whole striatum (1 SD) also showed reasonable agreement with the clinical classification (Cohen’s Kappa = 0.55), albeit with more ‘false positives’ classified in the quantitative group. Processing speed and functional outcome relate to 123I-Ioflupane scan abnormalities Over the whole group, TBI patients showed impaired performance in a range of cognitive domains, including tests of processing speed, memory and executive function when compared with the control group (Table 1). Patients also reported significantly increased apathy, fatigue and executive dysfunction compared to controls, a finding that was corroborated on caregiver questionnaires (Supplementary Table 2). Patients with significantly reduced caudate DaT levels as defined using the 2 SD criteria showed impairments in measures of processing speed of varying complexity compared to patients with normal caudate DaT levels. Specifically, abnormal patients were significantly slower on simple measures of processing speed including the Trail Making Test A (W = 177, P = 0.027) and Stroop Colour Naming and Word Reading Composite Score (W = 181.5, P = 0.045) as well as on the more complex Stroop Inhibition-Switching Task (W = 189.5, P = 0.022) (Supplementary Fig. 3). Functional outcomes as defined by the GOS-E were also worse in these patients (W = 66, P = 0.033). There were no differences in neuropsychological measures using the less stringent classification criterion (1 SD). Patients defined as abnormal on the clinical report did not show any difference on cognitive measures but did have worse outcome on the GOS-E (W = 130, P = 0.048). Changes in 123I-Ioflupane SBR in the whole striatum and putamen did not relate to cognitive measures. UPDRS score relates to 123I-Ioflupane scan abnormalities None of our patients had evidence of clear motor parkinsonism, which is usually the case after single TBI (Krauss and Jankovic, 2002). Despite this, six patients had high UPDRS motor subscale scores (>9) (Racette et al., 2006) (Fig. 6), which was due to pyramidal or cerebellar signs on examination. Patients with abnormal 123I-Ioflupane clinical reports had significantly higher UPDRS scores than patients with normal reports (W = 113, P = 0.002). This was also true for those patients with abnormal striatal (W = 90.5, P = 0.037) or abnormal caudate SBR using the 2 SD criteria (W = 51, P = 0.002). For the caudate, this relationship was also present with the less stringent 1 SD criteria (W = 151, P = 0.027). Putamen SBR did not relate to UPDRS score using either classification (both P > 0.2). Figure 6 Open in new tabDownload slide Characteristics of patients with UPDRS motor subscore >9. Clinical details of the six patients with UPDRS scores >9. Examination findings are included along with a functional outcome measure (Glasgow Outcome Scale-Extended, GOS-E), UPDRS score and an axial slice of their 123I-Ioflupane scan. Figure 6 Open in new tabDownload slide Characteristics of patients with UPDRS motor subscore >9. Clinical details of the six patients with UPDRS scores >9. Examination findings are included along with a functional outcome measure (Glasgow Outcome Scale-Extended, GOS-E), UPDRS score and an axial slice of their 123I-Ioflupane scan. Patients showed reduced volume of the substantia nigra and all subdivisions of the striatum The substantia nigra was significantly smaller in patients compared to controls [t(51.3) = −3.54, P < 0.001] (Fig. 7A). In addition, all three striatal subregions were significantly smaller in patients compared to controls; caudate [t(37.69) = −3.45, P = 0.001], putamen [t(46.0) = −4.26, P < 0.001] and nucleus accumbens [t(49.5) = −4.17, P < 0.001]. Figure 7 Open in new tabDownload slide Volumetric and diffusion tensor MRI results. (A) Volumetric assessment. Top line of plots shows volume corrected for intracranial volume for patients and controls in the substantia nigra, caudate, putamen and nucleus accumbens. Bottom two plots show 123I-Ioflupane SBR of the caudate and putamen (corrected for age) correlate positively with substantia nigra volume (corrected for age and intracranial volume). Patients are in red and controls in blue. The SBR and volumes corrected for age are the residuals from the linear regression of age on SBR and volume. Key at the bottom shows masks used for volumetric analysis of the different regions. (B) Diffusivity assessment. Top line of plots shows mean diffusivity corrected for age for patients and controls in the nigro-striatal, nigro-caudate, nigro-putamen and nigro-nucleus accumbens tracts. Bottom two plots show 123I-Ioflupane SBR of the whole striatum and caudate (corrected for age) correlate negatively with the mean diffusivity of the nigro-striatal and nigro-caudate tracts (corrected for age), respectively. Patients are in red and controls in blue. **P < 0.01; rs = Spearman’s rho, MD = mean diffusivity. The SBR and mean diffusivities corrected for age are the residuals from the linear regression of age on SBR and mean diffusivity. Key at the bottom shows the masks used for the nigro-putamen, nigro-caudate and nigro-nucleus accumbens tracts (the nigro-striatal tract was all three combined). Figure 7 Open in new tabDownload slide Volumetric and diffusion tensor MRI results. (A) Volumetric assessment. Top line of plots shows volume corrected for intracranial volume for patients and controls in the substantia nigra, caudate, putamen and nucleus accumbens. Bottom two plots show 123I-Ioflupane SBR of the caudate and putamen (corrected for age) correlate positively with substantia nigra volume (corrected for age and intracranial volume). Patients are in red and controls in blue. The SBR and volumes corrected for age are the residuals from the linear regression of age on SBR and volume. Key at the bottom shows masks used for volumetric analysis of the different regions. (B) Diffusivity assessment. Top line of plots shows mean diffusivity corrected for age for patients and controls in the nigro-striatal, nigro-caudate, nigro-putamen and nigro-nucleus accumbens tracts. Bottom two plots show 123I-Ioflupane SBR of the whole striatum and caudate (corrected for age) correlate negatively with the mean diffusivity of the nigro-striatal and nigro-caudate tracts (corrected for age), respectively. Patients are in red and controls in blue. **P < 0.01; rs = Spearman’s rho, MD = mean diffusivity. The SBR and mean diffusivities corrected for age are the residuals from the linear regression of age on SBR and mean diffusivity. Key at the bottom shows the masks used for the nigro-putamen, nigro-caudate and nigro-nucleus accumbens tracts (the nigro-striatal tract was all three combined). Substantia nigra volume is related to 123I-Ioflupane specific binding ratios Substantia nigra volume was related to caudate and putamen SBR. Linear regression showed substantia nigra volume was related to caudate SBR [b = 3.38, standard error (SE) = 1.63, t = 2.07, P = 0.04], such that low volume was associated with low SBR (Fig. 7A). There was no significant interaction between group and substantia nigra volume (P = 0.76), but the relationship was present when examining the patient group alone (b = 3.83, SE = 1.86, t = 2.06, P = 0.04). Substantia nigra volume was also related to putamen SBR (b = 3.28, SE = 1.63, t = 2.01, P = 0.04). Again, there was no interaction between group and substantia nigra volume (P = 0.77). Substantia nigra volume was not related to nucleus accumbens SBR, although the relationship was close to significance (P = 0.06). The volumes of the caudate, putamen and nucleus accumbens were not related to their respective SBRs (caudate P = 0.58, putamen P = 0.26, nucleus accumbens P = 0.21). Patients show damaged nigrostriatal connections to the caudate We next examined nigrostriatal tract structure, defined from analysis of high-resolution Human Connectome Project data. Patients showed significantly higher mean diffusivity in the white matter area through which the nigrostriatal tract passes [t(63.2) = 3.39, P = 0.001] (Fig. 7B). There was no difference in fractional anisotropy between patients and controls [t(41.6) = −0.69, P = 0.494]. We explored connections to subregions within the striatum. A mixed-effects model showed an interaction between tract and group [F(2,120) = 8.7, P < 0.001], which resulted from a significantly higher mean diffusivity in the nigro-caudate tract for patients compared to controls [t(57.9) = 3.48, P < 0.001] with no difference in the nigro-putamen (P = 0.3) or nigro-nucleus accumbens tracts (P = 0.2). Analyses of fractional anisotropy in these tracts did not reveal any differences between the groups (nigro-caudate tract, P = 0.4; nigro-putamen tract, P = 0.08; nigro-nucleus accumbens tract, P = 0.3). Nigrostriatal tract structure is related to substantia nigra volume Linear regression showed substantia nigra volume was related to mean diffusivity in the nigrostriatal tract (b = −0.31, SE = 0.10, t = −3.11, P = 0.003), such that low volume was associated with high mean diffusivity. In contrast, there was no significant relationship between mean diffusivity in the nigrostriatal tract and striatal SBR (P = 0.081) or between mean diffusivity in the nigro-caudate tract and caudate SBR (P = 0.078), although both these relationships approached significance. The presence of frontal lobe or striatal lesions does not alter striatal specific binding ratio Twenty-three patients had visible frontal lobe lesions on T1 imaging. These patients did not have a significant reduction in SBR in the whole striatum or its subregions compared to patients with no frontal lobe lesions and controls. In addition, there was no relationship between the size of frontal lobe lesions and SBR in the whole striatum or its subregions. Six patients had visible lesions in their caudate, three in the putamen and two in the nucleus accumbens. Patients with lesions in these structures did not have different SBRs compared to patients without lesions (caudate P = 0.46, putamen P = 0.97, nucleus accumbens P = 0.38). Discussion One third of our patients with moderate–severe TBI had abnormal striatal DaT on clinical reporting of 123I-Ioflupane SPECT scans. The caudate was affected to a greater extent than other striatal regions. However, at the individual level there was a large degree of variability, with some patients showing clear abnormalities in the other regions of the striatum. DaT abnormalities in the caudate were associated with reduced substantia nigra volume, and there was evidence of nigrostriatal tract damage particularly affecting projections to the caudate. Taken together our results suggest that the dopaminergic system is commonly affected by TBI. The caudate is most commonly affected although all areas of the striatum can be disrupted. Within individuals, the pattern of striatal abnormality is likely to reflect the location of nigrostriatal tract damage produced by axonal and midbrain damage. Our findings extend the two previous imaging studies in humans demonstrating altered DaT levels in the striatum after TBI (Donnemiller et al., 2000; Wagner et al., 2014). Donnemiller et al. (2000) found >50% reduction in striatal DaT binding using the SPECT tracer 123I-β-CIT in a group of 10 patients who were in a vegetative state or had persisting akinetic-rigid features. Wagner et al. (2014) studied a less severe group of 12 moderate–severe TBI patients and found a 15% striatal reduction using the PET ligand 11C-β-CFT. Our patients were of similar severity to Wagner’s study and we showed a similar magnitude of reduction in DaT (11% for whole striatum). Therefore, the three studies together suggest that reductions in striatal DaT are dependent on injury severity. Our results are also in line with animal models of TBI, which show reduced DaT expression in the striatum (Yan et al., 2002; Wagner et al., 2005b; Shimada et al., 2014). The DaT resides on presynaptic dopaminergic neurons, therefore loss of dopaminergic fibres results in reduced DaT levels. In addition, synaptic dopamine levels rapidly affect DaT expression (Gulley and Zahniser, 2003). Therefore, the hypodopaminergic state seen post-traumatically will lead to a compensatory downregulation in DaT expression (Bales et al., 2009). Animal work suggests that functional down regulation is the main driver of reduced DaT levels post-traumatically as other markers of dopaminergic cell density were unaffected (Wagner et al., 2005b). Our SPECT results are compatible with functional downregulation of DaT, but the MRI assessment suggests that dopaminergic cell loss may also be a factor. Reduced substantia nigra volume indicates cell loss in this region, which correlates with striatal DaT binding. This is likely to be at least partly due to direct damage to the cell bodies in the nuclei themselves. Brainstem nuclei are susceptible to the effects of trauma (Adams et al., 1989). Focal injury is often seen in the midbrain and computational models of TBI demonstrate high strain in the midbrain as the brain pivots in this region (Zhang et al., 2001). In addition, neuropathological studies in humans who have suffered repetitive head injuries show gross and microscopic changes to the substantia nigra (Smith et al., 2013). In addition to direct damage to the midbrain nuclei, dopaminergic neurons may suffer axonal injury to their projecting fibres leading to Wallerian degeneration and subsequent cell death of substantia nigra neurons. Animal models show that substantia nigra damage can be produced as a remote effect of cortical injury (van Bregt et al., 2012). This can result from damage to long-distance axonal projections that are vulnerable to the deforming forces generated by the acceleration and deceleration of the brain during trauma (Gennarelli et al., 1982). The ascending nigrostriatal dopaminergic axons may be particularly vulnerable as they are poorly or unmyelinated (Reeves et al., 2005; Staal and Vickers, 2011). We used high resolution diffusion MRI data from the Human Connectome Project to define the locations of the nigrostriatal projections and applied the results to assess nigrostriatal tract damage. A limitation of the diffusion results is that the nigrostriatal tracts cannot be specifically resolved and only make up a small percentage of the fibres in the white matter area studied. However, diffusion abnormalities were seen in the white matter through which the nigrostriatal tract passes. This reduction correlated with substantia nigra volume, suggesting that cell death in this region was linked to axonal injury within the nigrostriatal tract. A striking feature of our results is that post-traumatic changes in DaT levels were predominantly seen in the caudate. This was not due to focal injury within the caudate, as few patients had visible lesions in their striatum and there was no relationship between lesion presence and DaT SBRs. In addition, we didn’t observe a more subtle relationship between the volume of striatal subregions and DaT SBRs that would indicate a non-specific effect of atrophy. In contrast, our results provided evidence that caudate DaT might be particularly disrupted because of the high levels of damage within nigrostriatal fibres projecting to the caudate. Taken together the pattern of nigrostriatal tract damage and the relationship between tract damage, substantia nigra volumes and DaT binding suggests that nigrostriatal projections to the caudate might be particularly vulnerable following TBI and that damage to these projections preferentially reduces caudate dopamine after TBI. TBI patients with very low levels of caudate DaT showed evidence of processing speed and executive function abnormalities. Similar relationships between dopaminergic function and cognition have been shown in healthy individuals (Mozley et al., 2001), patients with Parkinson’s disease (Marie et al., 1999; Muller et al., 2000) and patients with Huntington’s disease (Backman et al., 1997). Executive functions and processing speed are thought to rely on intact functioning of cortico-striatal circuitry, which links the frontal cortex and caudate and is mediated by dopaminergic neurotransmission (Divac et al., 1967; Backman et al., 1997). Dopaminergic therapies in Parkinson’s disease ameliorate at least some of the associated cognitive impairments (Cools et al., 2002; Mattay et al., 2002). Therefore, TBI patients with evidence of dopaminergic dysfunction may benefit from dopaminergic medications for cognitive impairments and DaT neuroimaging might be a useful way to predict treatment response or stratify treatment selection. Previous work has shown TBI patients with obvious parkinsonism display striatal DaT abnormalities (Donnemiller et al., 2000). Here none of our patients were parkinsonian, which is the case for the vast majority of TBI patients (Krauss and Jankovic, 2002). Despite the absence of parkinsonism, our patients showed frequent evidence of striatal dopamine abnormalities. The lack of parkinsonism might reflect the location of striatal dopaminergic abnormalities, which were more pronounced in the caudate. Dopaminergic depletion in Parkinson’s disease initially occurs in the posterior putamen and reduced DaT levels in this region relate to motor signs (Guttman et al., 1997; Ma et al., 2002). At the group level, our patients did not have a significant reduction of DaT in the putamen. However, some individuals had clear reductions in putaminal DaT levels. This might be due to the severity of dopaminergic changes. At the time of symptom onset in Parkinson’s disease there is usually over 50% reduction in DaT levels (Cheng et al., 2010). None of our patients had reductions in DaT to this degree, therefore the impact of TBI on the dopaminergic system maybe below the threshold required to display overt signs of parkinsonism. However, TBI patients with evidence of reductions in DaT levels might be predisposed to the future development of parkinsonism. Our work does not provide information about the long-term significance of reduced DaT, which is a limitation of the cross-sectional study design. Further longitudinal studies will be needed to inform how these abnormalities evolve and to what extent DaT abnormalities are a risk factor for late deterioration. Our in vivo imaging assessment uses a semi-quantitative technique, which assumes that non-specific uptake of 123I-Ioflupane is equivalent throughout the brain. Therefore, if TBI caused variable changes to this non-specific uptake in different brain regions (e.g. through changes to striatal absorption of 123I-Ioflupane) this could bias the results. We have no reason to suspect distinct non-specific uptake across the striatum to explain the pattern of abnormalities we observed and our results are also in line with animal models of TBI using different techniques, which also show reduced DaT expression in the striatum (Yan et al., 2002; Wagner et al., 2005b; Shimada et al., 2014). In conclusion, striatal DaT abnormalities measured using 123I-ioflupane SPECT were commonly seen following moderate–severe TBI. One third of the SPECT scans were clinically reported as abnormal. These changes are a marker of reduced striatal dopamine. Our results suggest this is due to the pattern of nigrostriatal tract damage produced by axonal injury. Cognitive impairment was greater in patients with marked reductions in caudate DaT and similar cognitive impairments respond to dopaminergic treatments in other contexts. Therefore, DaT abnormalities following TBI may assist treatment selection after TBI. Funding D.J.S. is funded by a National Institute of Health Research Professorship (NIHR-RP-011-048). P.O.J. is funded by Guarantors of Brain Clinical Fellowship. The research was also supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre. Supplementary material Supplementary material is available at Brain online. Abbreviations Abbreviations DaT dopamine transporter SBR specific binding ratio SPECT single-photon emission computed tomography TBI traumatic brain injury UPDRS Unified Parkinson’s Disease Rating Scale References Adams JH , Doyle D , Ford I , Gennarelli TA , Graham DI , McLellan DR . Diffuse axonal injury in head injury: definition, diagnosis and grading . Histopathology 1989 ; 15 : 49 – 59 . Google Scholar Crossref Search ADS PubMed WorldCat Ashburner J . A fast diffeomorphic image registration algorithm . Neuroimage 2007 ; 38 : 95 – 113 . Google Scholar Crossref Search ADS PubMed WorldCat Backman L , Robins-Wahlin TB , Lundin A , Ginovart N , Farde L . Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes . Brain 1997 ; 120 (Pt 12) : 2207 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat Bales JW , Wagner AK , Kline AE , Dixon CE . Persistent cognitive dysfunction after traumatic brain injury: a dopamine hypothesis . Neurosci Biobehav Rev 2009 ; 33 : 981 – 1003 . Google Scholar Crossref Search ADS PubMed WorldCat Benamer HT , Oertel WH , Patterson J , Hadley DM , Pogarell O , Hoffken H , et al. Prospective study of presynaptic dopaminergic imaging in patients with mild parkinsonism and tremor disorders: part 1. Baseline and 3-month observations . Mov Disord 2003 ; 18 : 977 – 84 . Google Scholar Crossref Search ADS PubMed WorldCat Bjorklund A , Dunnett SB . Dopamine neuron systems in the brain: an update . Trends Neurosci 2007 ; 30 : 194 – 202 . Google Scholar Crossref Search ADS PubMed WorldCat Cheng HC , Ulane CM , Burke RE . Clinical progression in Parkinson disease and the neurobiology of axons . Ann Neurol 2010 ; 67 : 715 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Cools R , Stefanova E , Barker RA , Robbins TW , Owen AM . Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of the prefrontal cortex revealed by PET . Brain 2002 ; 125 (Pt 3) : 584 – 94 . Google Scholar Crossref Search ADS WorldCat Divac I , Rosvold HE , Szwarcbart MK . Behavioral effects of selective ablation of the caudate nucleus . J Comp Physiol Psychol 1967 ; 63 : 184 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Donnemiller E , Brenneis C , Wissel J , Scherfler C , Poewe W , Riccabona G , et al. Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPECT study using 123I-beta-CIT and 123I-IBZM . Eur J Nucl Med 2000 ; 27 : 1410 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Ekman U , Eriksson J , Forsgren L , Mo SJ , Riklund K , Nyberg L . Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study . Lancet Neurol 2012 ; 11 : 679 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat Gennarelli TA , Thibault LE , Adams JH , Graham DI , Thompson CJ , Marcincin RP . Diffuse axonal injury and traumatic coma in the primate . Ann Neurol 1982 ; 12 : 564 – 74 . Google Scholar Crossref Search ADS PubMed WorldCat Goetz CG , Fahn S , Martinez-Martin P , Poewe W , Sampaio C , Stebbins GT , et al. Movement disorder society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): process, format, and clinimetric testing plan . Mov Disord 2007 ; 22 : 41 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Grace J , Malloy PF . Frontal systems behaviour scale: professional manual . Lutz , FL : Psychological Assessment Resources, Inc. ; 2001 . Google Preview WorldCat COPAC Gulley JM , Zahniser NR . Rapid regulation of dopamine transporter function by substrates, blockers and presynaptic receptor ligands . Eur J Pharmacol 2003 ; 479 : 139 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat Guttman M , Burkholder J , Kish SJ , Hussey D , Wilson A , DaSilva J , et al. [11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson's disease: implications for the symptomatic threshold . Neurology 1997 ; 48 : 1578 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat Huger F , Patrick G . Effect of concussive head injury on central catecholamine levels and synthesis rates in rat brain regions . J Neurochem 1979 ; 33 : 89 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Kehagia AA , Barker RA , Robbins TW . Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease . Lancet Neurol 2010 ; 9 : 1200 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat Keuken MC , Bazin PL , Crown L , Hootsmans J , Laufer A , Muller-Axt C , et al. Quantifying inter-individual anatomical variability in the subcortex using 7 T structural MRI . Neuroimage 2014 ; 94 : 40 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Kinnunen KM , Greenwood R , Powell JH , Leech R , Hawkins PC , Bonnelle V , et al. White matter damage and cognitive impairment after traumatic brain injury . Brain 2011 ; 134(Pt 2) : 449 – 63 . Google Scholar Crossref Search ADS WorldCat Kobori N , Clifton GL , Dash PK . Enhanced catecholamine synthesis in the prefrontal cortex after traumatic brain injury: implications for prefrontal dysfunction . J Neurotrauma 2006 ; 23 : 1094 – 102 . Google Scholar Crossref Search ADS PubMed WorldCat Krauss JK , Jankovic J . Head injury and posttraumatic movement disorders . Neurosurgery 2002 ; 50 : 927 – 39 ; discussion 939–40 . Google Scholar PubMed WorldCat Lee KA , Hicks G , Nino-Murcia G . Validity and reliability of a scale to assess fatigue . Psychiatry Res 1991 ; 36 : 291 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Ma Y , Dhawan V , Mentis M , Chaly T , Spetsieris PG , Eidelberg D . Parametric mapping of [18F]FPCIT binding in early stage Parkinson's disease: a PET study . Synapse 2002 ; 45 : 125 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat Malec JF , Brown AW , Leibson CL , Flaada JT , Mandrekar JN , Diehl NN , et al. The mayo classification system for traumatic brain injury severity . J Neurotrauma 2007 ; 24 : 1417 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat Marek KL , Seibyl JP , Zoghbi SS , Zea-Ponce Y , Baldwin RM , Fussell B , et al. [123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease . Neurology 1996 ; 46 : 231 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Marie RM , Barre L , Dupuy B , Viader F , Defer G , Baron JC . Relationships between striatal dopamine denervation and frontal executive tests in Parkinson's disease . Neuroscience Letters 1999 ; 260 : 77 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat Massucci JL , Kline AE , Ma X , Zafonte RD , Dixon CE . Time dependent alterations in dopamine tissue levels and metabolism after experimental traumatic brain injury in rats . Neurosci Lett 2004 ; 372 : 127 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Mattay VS , Tessitore A , Callicott JH , Bertolino A , Goldberg TE , Chase TN , et al. Dopaminergic modulation of cortical function in patients with Parkinson's disease . Ann Neurol 2002 ; 51 : 156 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat McIntosh TK , Yu T , Gennarelli TA . Alterations in regional brain catecholamine concentrations after experimental brain injury in the rat . J Neurochem 1994 ; 63 : 1426 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat Mozley LH , Gur RC , Mozley PD , Gur RE . Striatal dopamine transporters and cognitive functioning in healthy men and women . Am J Psychiatry 2001 ; 158 : 1492 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Muller U , Wachter T , Barthel H , Reuter M , von Cramon DY . Striatal [123I]beta-CIT SPECT and prefrontal cognitive functions in Parkinson's disease . J Neural Transm 2000 ; 107 : 303 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat Nichols TE , Holmes AP . Nonparametric permutation tests for functional neuroimaging: a primer with examples . Hum Brain Mapp 2002 ; 15 : 1 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Racette BA , Tabbal SD , Jennings D , Good LM , Perlmutter JS , Evanoff BA . A rapid method for mass screening for parkinsonism . Neurotoxicology 2006 ; 27 : 357 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat Reeves TM , Phillips LL , Povlishock JT . Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury . Exp Neurol 2005 ; 196 : 126 – 37 . Google Scholar Crossref Search ADS PubMed WorldCat Shimada R , Abe K , Furutani R , Kibayashi K . Changes in dopamine transporter expression in the midbrain following traumatic brain injury: an immunohistochemical and in situ hybridization study in a mouse model . Neurol Res 2014 ; 36 : 239 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat Smith DH , Johnson VE , Stewart W . Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol 2013 ; 9 : 211 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Smith SM , Nichols TE . Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference . Neuroimage 2009 ; 44 : 83 – 98 . Google Scholar Crossref Search ADS PubMed WorldCat Sockeel P , Dujardin K , Devos D , Deneve C , Destee A , Defebvre L . The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease . J Neurol Neurosurg Psychiatry 2006 ; 77 : 579 – 84 . Google Scholar Crossref Search ADS PubMed WorldCat Staal JA , Vickers JC . Selective vulnerability of non-myelinated axons to stretch injury in an in vitro co-culture system . J Neurotrauma 2011 ; 28 : 841 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Tournier JD , Calamante F , Connelly A . MRtrix: diffusion tractography in crossing fiber regions . Int J Imag Syst Tech 2012 ; 22 : 53 – 66 . Google Scholar Crossref Search ADS WorldCat van Bregt DR , Thomas TC , Hinzman JM , Cao T , Liu M , Bing G , et al. Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat . Exp Neurol 2012 ; 234 : 8 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat Van Essen DC , Smith SM , Barch DM , Behrens TE , Yacoub E , Ugurbil K , et al. The WU-Minn Human Connectome Project: an overview . Neuroimage 2013 ; 80 : 62 – 79 . Google Scholar Crossref Search ADS PubMed WorldCat Wagner AK , Chen X , Kline AE , Li Y , Zafonte RD , Dixon CE . Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury . Exp Neurol 2005a ; 195 : 475 – 83 . Google Scholar Crossref Search ADS WorldCat Wagner AK , Drewencki LL , Chen X , Santos FR , Khan AS , Harun R , et al. Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury . J Neurochem 2009 ; 108 : 986 – 97 . Google Scholar Crossref Search ADS PubMed WorldCat Wagner AK , Scanlon JM , Becker CR , Ritter AC , Niyonkuru C , Dixon CE , et al. The influence of genetic variants on striatal dopamine transporter and D2 receptor binding after TBI . J Cereb Blood Flow Metab 2014 ; 34 : 1328 – 39 . Google Scholar Crossref Search ADS PubMed WorldCat Wagner AK , Sokoloski JE , Ren D , Chen X , Khan AS , Zafonte RD , et al. Controlled cortical impact injury affects dopaminergic transmission in the rat striatum . J Neurochem 2005b ; 95 : 457 – 65 . Google Scholar Crossref Search ADS WorldCat Wenning GK , Donnemiller E , Granata R , Riccabona G , Poewe W . 123I-beta-CIT and 123I-IBZM-SPECT scanning in levodopa-naive Parkinson's disease . Mov Disord 1998 ; 13 : 438 – 45 . Google Scholar Crossref Search ADS PubMed WorldCat Wilson JT , Pettigrew LE , Teasdale GM . Structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: guidelines for their use . J Neurotrauma 1998 ; 15 : 573 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat Wilson MS , Chen X , Ma X , Ren D , Wagner AK , Reynolds IJ , et al. Synaptosomal dopamine uptake in rat striatum following controlled cortical impact . J Neurosci Res 2005 ; 80 : 85 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat Yan HQ , Kline AE , Ma X , Li Y , Dixon CE . Traumatic brain injury reduces dopamine transporter protein expression in the rat frontal cortex . Neuroreport 2002 ; 13 : 1899 – 901 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang H , Avants BB , Yushkevich PA , Woo JH , Wang S , McCluskey LF , et al. High-dimensional spatial normalization of diffusion tensor images improves the detection of white matter differences: an example study using amyotrophic lateral sclerosis . IEEE Trans Med Imaging 2007 ; 26 : 1585 – 97 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang L , Yang KH , King AI . Comparison of brain responses between frontal and lateral impacts by finite element modeling . J Neurotrauma 2001 ; 18 : 21 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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TI - Dopaminergic abnormalities following traumatic brain injury
JO - Brain
DO - 10.1093/brain/awx357
DA - 2018-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/dopaminergic-abnormalities-following-traumatic-brain-injury-v2GbbnGiUX
SP - 797
VL - 141
IS - 3
DP - DeepDyve
ER -