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Bilateral arm raising movements have been used in brain rehabilitation for a long time. However, no study has been reported on the effect of these movements on the cerebral cortex. In this study, using functional near infrared spectroscopy (fNIRS), we attempted to investigate cortical activation generated during bilateral arm raising movements. Ten normal subjects were recruited for this study. fNIRS was performed using an fNIRS system with 49 channels. Bilateral arm raising movements were performed in sitting position at the rate of 0.5 Hz. We measured values of oxyhemoglobin and total hemoglobin in five regions of interest: the primary sensorimotor cortex, premotor cortex, supplementary motor area, prefrontal cortex, and posterior parietal cortex. During performance of bilateral arm raising movements, oxyhemoglobin and total hemoglobin values in the primary sensorimotor cortex, premotor cortex, supplementary motor area, and prefrontal cortex were similar, but higher in these regions than those in the prefrontal cortex. We observed activation of the arm somatotopic areas of the primary sensorimotor cortex and premotor cortex in both hemispheres during bilateral arm raising movements. According to this result, bilateral arm raising movements appeared to induce large-scale neuronal activation and therefore arm raising movements would be good exercise for recovery of brain functions.

Mental practice is a new rehabilitation method that refers to the mental rehearsal of motor imagery content with the goal of improving motor performance. However, the relationship between activated regions and motor recovery after mental practice training is not well understood. In this study, 15 patients who suffered a first-ever subcortical stroke with neurological deficits affecting the right hand, but no significant cognitive impairment were recruited. 10 patients underwent mental practice combined with physical practice training, and 5 patients only underwent physical practice training. We observed brain activation regions after 4 weeks of training, and explored the correlation of activation changes with functional recovery of the affected hands. The results showed that, after 4 weeks of mental practice combined with physical training, the Fugl-Meyer assessment score for the affected right hand was significantly increased than that after 4 weeks of practice training alone. Functional MRI showed enhanced activation in the left primary somatosensory cortex, attenuated activation intensity in the right primary motor cortex, and enhanced right cerebellar activation observed during the motor imagery task using the affected right hand after mental practice training. The changes in brain cortical activity were related to functional recovery of the hand. Experimental findings indicate that cortical and cerebellar functional reorganization following mental practice contributed to the improvement of hand function.

The corticospinal tract (CST) is a neural tract responsible for motor function in the human brain. It is mainly related to hand movements (Jang, 2014). Therefore, recovery of an injured CST contributes to good recovery in stroke patients and a thorough knowledge of the recovery mechanism regarding an injured CST is required for successful brain rehabilitation.

Motor weakness is a common and important sequela of stroke, and motor recovery is mostly achieved within 3 months following stroke (Jorgensen et al., 1995; Fujii and Nakada, 2003), suggesting the importance of active rehabilitation during the early stage of stroke. Many studies have reported on neurological recovery during this period, however, little is known about pontine infarction (Jang et al., 2007; Kwon and Jang, 2012; Kwon et al., 2013; Yeo and Jang, 2013; Chang et al., 2014; Jang and Yeo, 2014; Seo and Jang, 2015). In this study, we attempted to demonstrate the recovery of an injured corticospinal tract (CST) using diffusion tensor tractography (DTT) and transcranial magnetic stimulation (TMS) during the early stage of rehabilitation following pontine infarction.

The corticospinal tract (CST) is a major neuronal tract of motor function in the human brain (York, 1987; Davidoff, 1990; Jang, 2014). Recovery of an injured CST is one of the motor recovery mechanisms in stroke patients (Hendricks et al., 2003; Jang et al., 2006, 2007; Swayne et al., 2008; Kwon et al., 2011, 2013; Kwon and Jang, 2012; Yeo and Jang, 2013; Rong et al., 2014). Diffusion tensor tractography (DTT), derived from diffusion tensor imaging (DTI), and transcranial magnetic stimulation (TMS) have been widely used in demonstrating the recovery of an injured CST (Hendricks et al., 2003; Jang et al., 2006, 2007; Swayne et al., 2008; Pannek et al., 2009; Kwon et al., 2011, 2013; Kwon and Jang, 2012; Yeo and Jang, 2013; Rong et al., 2014). DTT has the advantage of enabling visualization of the architecture and integrity of the CST at the subcortical level in three dimensions (Mori et al., 1999; Kunimatsu et al., 2004). TMS has a unique advantage in that it can be used to evaluate change of the CST by analysis of the characteristics of the motor-evoked potential (MEP) (Rossini et al., 1994). The advantages of each method for evaluating the recovery of an injured CST allow more accurate estimation when they are employed concomitantly (Rossini et al., 1994; Kunimatsu et al., 2004; Jang, 2009). Many studies have demonstrated the recovery of an injured CST using DTT and TMS (Hendricks et al., 2003; Jang et al., 2006, 2007; Swayne et al., 2008; Pannek et al., 2009; Kwon et al., 2011; Kwon and Jang, 2012; Yang et al.,2008; Yeo and Jang, 2013; Rong et al., 2014). However, little is known about the recovery of a degenerated CST after injury in stroke patients (Jung, 2012). In this study, we demonstrated the recovery of a degenerated CST after injury in a patient with intracerebral hemorrhage (ICH), using DTT and TMS. A 51-year-old, right-handed asian male patient suffered spontaneous left side motor weakness. He underwent craniotomy and removal of hematoma, which resulted from the right putaminal hemorrhage, at the department of neurosurgery of a university hospital. At 6 weeks after onset of ICH, he was transferred to the rehabilitation department of another university hospital to undergo rehabilitation therapy in order to gain function regardless of their deficiencies. Brain CT, taken at onset, showed a hematoma in the right putamen, and brain MRI, scanned at 6 weeks after onset, showed a leukomalactic lesion at the left corona radiata and basal ganglia due to a previous putaminal ICH which had been neglected without exact diagnosis and was diagnosed as an old ICH by a neuroradiologist at this time (Figure 1A). Figure 1 Brain CT, MRI, diffusion tensor tractography, and motor-evoked potential of a patient with intracerebral hemorrhage. The standardized Motricity Index (MI) and Medical Research Council (MRC) were used for determination of motor function of the affected extremities (Gregson et al., 2000). The MI, with a maximum score of 100, is a measure of the integrity of the motor function of an extremity. The reliability and validity of the MI are well established (Demeurisse et al., 1980). MRC: 0, no contraction; 1, palpable contraction, but no visible movement; 2, movement without gravity, 3, movement against gravity; 4, movement against a resistance lower than the resistance overcome by the healthy side; 5, movement against a resistance equal to the maximum resistance overcome by the healthy side. He presented with complete weakness of the left upper and lower extremities at onset of ICH (MI: 0) (Table 1). For approximately 8.5 months, from 6 weeks to 10 months after onset, he received comprehensive rehabilitative management in the university hospital and a local rehabilitation hospital, including administration of neurotrophic drugs (methylphenidate 10 mg, pramipexole 1 mg, bromocriptine 10 mg, levodopa 750 mg, and amantadine 300 mg), movement therapy, procedures for spasticity control of the left finger flexors, and neuromuscular electrical stimulation of the left finger extensors and ankle dorsiflexors (Scheidtmann et al., 2001). Movement therapy focused on improvement of the motor function of the left upper and lower extremities and was performed five times per week. The patient recovered from severe weakness of the left upper and lower extremities: MI scores at the indicated times: stroke onset 0 points; 6 weeks: 31 points; 4 months, 51 points; 10 months, 64 points (Table 1). As a result, he regained the ability to perform grasp-release using the left hand and to walk independently. The patient provided signed, informed consent and our institutional review board approved the study protocol. Table 1 Changes of motor function in the patient with intracerebral hemorrhage DTI data were acquired three times (6 weeks, 4 and 10 months after onset) using a 1.5 T Philips Gyroscan Intera system (Philips, Ltd, Best, the Netherlands) with single-shot echo-planar imaging. Seventy contiguous slices were acquired parallel to the anterior commissure-posterior commissure line for each of the 32 non-collinear diffusion sensitizing gradients. Imaging parameters were as follows: acquisition matrix = 96 × 96, repetition time = 10,398 ms, echo time = 72 ms, echo planar imaging factor = 59 and b = 1,000 s/mm2, number of excitations = 1, and slice thickness = 2.5 mm. The fiber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software was used for fiber tracking (Mori et al., 1999). Fibers passing through two regions of interest (ROIs) at the upper and lower pons (portion of anterior blue color) were selected for CSTs (fractional anisotropy threshold: > 0.15, direction threshold: < 27° (Kunimatsu et al., 2004; Kwon and Jang, 2011). Magstim Novametrix 200 magnetic stimulator with a 9-cm mean diameter circular coil was used for TMS study (Novametrix Inc. 45 WEST ST, suite 2, Attleboro, MA, USA). Counterclockwise current was employed for stimulation of the left hemisphere, and a clockwise current for stimulation of the right hemisphere. MEPs were obtained at both abductor pollicis brevis muscles in a relaxed state. The minimum stimulus required to elicit an MEP with a peak-to-peak amplitude of 50 μV or greater in two out of four attempts was defined as the excitatory threshold. Stimulation intensity was fixed at the excitatory threshold + 20% of the maximum stimulator output. Results of DTT of the unaffected hemisphere showed that the CST originated from the cerebral cortex, including the primary motor cortex, and descended along the known CST pathway (Figure 1B). By contrast, discontinuation of the right CST in the brainstem was observed on 6-week DTT images. However, this discontinued right CST was elongated to the right primary motor cortex on 4-month DTT images and had become thicker on 10-month DTT images. We could not obtain any MEP from the right hemisphere stimulation at 6 weeks (Figure 1C). However, transcranial magnetic stimulation studies showed that at 4 and 10 months after injury, MEPs were evoked from the right hemisphere(4 months: latency 25.4 ms, amplitude 100 μV, excitatory threshold 100 %; 10 months: latency 22.9 ms, amplitude 270 μV, excitatory threshold 100 %). In this patient, we followed up the changes of the CST along with the motor recovery until 10 months after onset, using DTT and TMS, in terms of clinical aspect of motor recovery, change of DTT for the injured CST, and change of MEP on TMS study. Regarding the recovery of a degenerated CST after injury, in 2012, in 19 patients with ICH, Jung et al. reported that the discontinued CST which did not reach the hematoma at early stage (within 1 month after onset) showed recovery, like this patient, in three patients after 3 months from onset (Jung, 2012). Consequently, to the best of our knowledge, this is the first study to demonstrate the recovery of a degenerated CST after injury in a stroke patient, using DTT and TMS. However, limitations of DTI and TMS should be considered. Due to crossing fiber or partial volume effect, false positive or negative results can be obtained (Yamada, 2009). By contrast, TMS has the possibility of false negative results due to excessive high threshold at the early stage of stroke. In conclusion, we report on a patient with ICH who showed recovery of a degenerated CST after injury, using DTT and TMS. These results provide evidence that recovery can occur even in case of severe injury of the CST; therefore, results of this study have important significance for rehabilitation for stroke patients. This work was supported by the DIGIST R&D Program of the Ministry of Science, ICT and Future Planning (15-BD-0401).

We reported a 50-year-old female patient with left supplementary motor area infarction who presented right lower limb apraxia and investigated the possible causes using transcranial magnetic stimulation. The patient was able to walk and climb stairs spontaneously without any assistance at 3 weeks after onset. However, she was unable to intentionally move her right lower limb although she understood what she supposed to do. The motor evoked potential evoked by transcranial magnetic stimulation from the right lower limb was within the normal range, indicating that the corticospinal tract innervating the right lower limb was uninjured. Thus, we thought that her motor dysfunction was not induced by motor weakness, and confirmed her symptoms as apraxia. In addition, these results also suggest that transcranial magnetic stimulation is helpful for diagnosing apraxia.

The cingulum, the neural tract connecting the orbitofrontal cortex with the medial temporal lobe, plays an important role in cognition (Bush et al., 2000). It is also important in memory because it provides cholinergic innervations to the cerebral cortex after obtaining innervation from the medial septal nucleus, the vertical nucleus of the diagonal band, and the nucleus basalis of Meynert via the medial cholinergic pathway (Nieuwenhuys et al., 2008; Naidich and Duvernoy, 2009; Hong and Jang, 2010a).

Over the past two decades, the development of functional imaging methods has greatly promoted our understanding on the changes of neurons following neurodegenerative disorders, such as Parkinson's disease (PD). The application of a spatial covariance analysis on 18F-FDG PET imaging has led to the identification of a distinctive disease-related metabolic pattern. This pattern has proven to be useful in clinical diagnosis, disease progression monitoring as well as assessment of the neuronal changes before and after clinical treatment. It may potentially serve as an objective biomarker on disease progression monitoring, assessment, histological and functional evaluation of related diseases. PD is one of the most common neurodegenerative disorders in the elderly. It is characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta. Throughout the course of disease, the most obvious symptoms are movement-related, such as resting tremor, muscle rigidity, hypokinesia and postural instability (Worth, 2013). Currently, a definite diagnosis of PD is made by clinical evaluation with at least 2 years of follow-up (Hughes et al., 2002; Bhidayasiri and Reichmann, 2013), due to the overlap of motor symptoms between early PD and atypical parkinsonism including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). However, this classic diagnostic criterion does not benefit the early diagnosis of disease. The prognostic outcome and treatment option are substantially different between PD and atypical parkinsonism. Thus it is critical to develop biomarkers for earlier and more accurate diagnosis of PD. Generally, appropriate diagnostic biomarker for PD ought to cover several key characteristics: (i) minimal invasiveness to detect the biomarker in easily accessible body tissue or fluids, (ii) excellent sensitivity to explore the patients with PD, (iii) high specificity to prevent false-positive results in PD-free individuals, and (iv) robustness against potential affecting factors. A PD-related spatial covariance pattern (PDRP) with quantifiable expression on 18F-FDG PET imaging has been gradually detected using a spatial covariance method during the last two decades and it has been demonstrated to be the right diagnostic biomarker for PD (Eidelberg et al., 1994). PDRP has proven not only to be effective in early discrimination of PD from atypical parkinsonian disorders, but also to be able to assess the disease progression and treatment response. Thus it is considered as a multifunctional biomarker. In this review, we aim to provide an overview of the development in pattern-based biomarker for PD.

Acute hemorrhagic anemia can decrease blood flow and oxygen supply to brain, and affect its physiological function. While detecting changes in brain function in patients with acute hemorrhagic anemia is helpful for preventing neurological complications and evaluating therapeutic effects, clinical changes in the nervous systems of these patients have not received much attention. In part, this is because current techniques can only indirectly detect changes in brain function following onset of anemia, which leads to lags between real changes in brain function and their detection. Some methods such as Transcranial Doppler can detect changes in cerebral blood-flow velocity that result from compensatory responses to the deficient oxygen delivery seen in anemia (i.e. higher velocity associated with anemia and lower velocity associated with recovery), but cannot reflect the actual oxygen supply and metabolism in the brain or organic changes such as stroke (Purkayastha and Sorond, 2012). Conventional CT and MRI can detect early cerebral infarction so as to facilitate early treatment, but cannot monitor physiological changes in the brain that occur because of anemia (Allmendinger et al., 2012). Near-infrared spectroscopy is a non-invasive method capable of measuring total blood-oxygen levels in brain (Murkin and Arango, 2009; Navarro et al., 2012; Yamazaki et al., 2013), but is unable to provide fine details concerning alterations in different cerebral tissues. Susceptibility-weighted imaging is a novel, non-invasive method for detecting changes in cerebral oxygen levels that may provide more detailed information regarding cerebral blood flow in patients with hemorrhage (Li et al., 2013). In the present study, we used susceptibility-weighted imaging to detect cerebral changes in an animal model of acute hemorrhagic anemia. Construction of the rabbit model of acute hemorrhagic anemia was based on the method used by Morimoto et al. (2001). A 40-mL blood sample was drawn through an arterial catheter. To compensate for the effects of simple blood-volume loss, the same volume of a 6% hydroxyethyl starch in 0.9% sodium chloride solution was injected through a femoral vein catheter. Following this, a blood sample was drawn again for blood-gas analysis and whole blood tests, and the head of the rabbit was re-scanned by MRI. The bloodletting, fluid infusion, and scanning processes were repeated continuously five times before the animal recovered from anesthesia; on the fifth occasion, the bloodletting volume and fluid-infusion volume were both 50 mL. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996), and the protocol was approved by the Institutional Animal Care Committee from Second People's Hospital of Shenzhen City, First Affiliated Hospital of Shenzhen University, China. The blood samples obtained from the femoral artery were used for blood-gas analysis, which determined the PaO2 PaCO2 lactic acid, and pH levels. In addition, mean arterial pressure was measured (Figure 1). A catheter was inserted through the femoral vein to the atrium for infusion of fluid, and red blood-cell count, hemoglobin concentration, hematocrit, and central venous pressure were assessed (Figure 1). There was an approximate halving of the red blood-cell count, hemoglobin concentration, and hematocrit values after the first bloodletting, and these values progressively decreased following each of the four subsequent bloodletting procedures. The values of these parameters after the fifth bloodletting were significantly lower than the pre-bleed values (P 0.05, vs. pre-bleed; Figure 1D). Figure 1 Results of whole blood tests, blood-gas analyses, mean arterial pressure, and central venous pressure after acute hemorrhagic anemia. The rabbits were fixed to a special board in the supine position and scanned by a Siemens Magnetom Avanto 1.5 T MRI Scanner, using a body coil (excitation) and wrap-around surface coil (reception). T2 dual-echo fast spin-echo with fat-suppression (FSE-T2WI/PD) and susceptibility-weighted imaging 3D sequences were used. The scan extended downward from a plane passing through the superior orbital margin to the medulla oblongata of the rabbit. FSE-T2WI/PD acquisition was conducted using the following parameters: repetition time = 2,800 ms, echo time = 33/78 ms, field of view = 12 cm × 12 cm, matrix size = 256 × 256; acquisition time = 3.09 minutes. Susceptibility-weighted imaging acquisition was performed with a three-dimensional gradient echo sequence, as follows: repetition time = 49 ms; echo time = 40 ms; flip angle = 15°; field of view = 15 cm × 15 cm; bandwidth = 80 kHz; IPAT factor = 2. Additional processing was carried out on the phase-corrected susceptibility-weighted imaging sequences. The third ventricle and the olfactory bulb parallel to the corpus callosum were measured. The bilateral frontal cortex, frontal white matter, temporal lobe, and thalamus were selected manually as regions of interest. The control (pre-bleed) susceptibility-weighted imaging-signal value of the frontal white matter was significantly lower than that of the frontal cortex (52.50 ± 20.29 vs. 63.10 ± 22.82; P 0.05). Susceptibility-weighted imaging signals from the frontal cortex, temporal lobe, and thalamus after the second, third, fourth and fifth bloodletting procedures were significantly lower compared with the corresponding control (pre-bleed) values (P < 0.05; Figures ​Figures2,2, ​,33). Figure 2 Representative susceptibility-weighted imaging (SWI) and corresponding T2-weighted images of a rabbit brain that was obtained at the superior aspect of the olfactory bulb (1a, 1b), the border of the olfactory bulb (2a, 2b), the thalamus (3a, 3b), and ... Figure 3 Effects of repeated bloodletting on the susceptibility-weighted imaging (SWI) signal values of selected regions of the rabbit brain. We also evaluated the overall cerebral white-gray contrast and vein structure to examine the susceptibility-weighted imaging minimum-intensity projection images. The contrast between cerebral gray and white matter was higher after bloodletting (particularly after the fourth and fifth procedures) than beforehand, and the venous structure was more abundant and clear (Figure 4). Figure 4 Susceptibility-weighted imaging (SWI) minimum-intensity projection images of the rabbit thalamus and cerebral veins obtained by magnetically-sensitive scanning after bloodletting. Hematoxylin and eosin staining showed that degeneration and necrosis of neurons and glial cells were not evident in the brains or cerebellums of our rabbits with acute hemorrhagic anemia (Figure 5). However, spaces had formed around blood vessels and cells, consistent with the occurrence of cerebral edema. Figure 5 Pathological changes in rabbit brain tissue after the fifth bloodletting (hematoxylin-eosin staining, × 100). In conclusion, this study has revealed that susceptibility-weighted imaging is an effective tool for detecting PaO2 and PaCO2-induced changes in cerebral oxygenation of different brain regions after acute hemorrhagic anemia. Therefore, susceptibility-weighted imaging may be a useful technique for monitoring the pathophysiologic changes and related complications associated with acute anemia.

Visual field defect is one of the various clinical manifestations in patients with subarachnoid hemorrhage (SAH). Little is known about the pathogenic mechanism of visual field defect in SAH. In the current study, we investigated the diffusion tensor imaging (DTI) finding of the optic radiation in patients with SAH following rupture of a cerebral artery aneurysm. We recruited 21 patients with aneurismal SAH (12 males, 9 females, mean age, 52.67 years; range, 41–68 years) who showed no definite lesion along the visual pathway. Twenty-one age-and sex-matched normal control subjects were also recruited. DTI data were acquired at an average of 5.9 weeks (range: 3–12 weeks) after onset and reconstruction of the optic radiation was performed using DTI-Studio software. The fractional anisotropy value, apparent diffusion coefficient value, and fiber number of the optic radiation were measured. The fractional anisotropy value of the optic radiation was significantly decreased, and the apparent diffusion coefficient value was significantly increased, in patients with aneurismal SAH than in normal control subjects. However, there was no significant difference in the fiber number of the optic radiation between patients with aneurismal SAH and normal control subjects. The decrement of fractional anisotropy value and increment of apparent diffusion coefficient value of the optic radiation in patients with aneurismal SAH suggest optic radiation injury. Therefore, we recommend a thorough evaluation for optic radiation injury in patient with aneurismal SAH.

The cingulum is the neural fiber bundle that connects the basal forebrain and medial temporal lobe. The cingulum contains the medial cholinergic pathway, which originates from the basalis nucleus of Meynert in the basal forebrain. Therefore, it is important for memory function (Malykhin et al., 2008; Hong and Jang, 2010). In the past, identification of the cingulum on conventional brain MRI has been impossible because it cannot discern the cingulum from other adjacent structures. Diffusion tensor tractography (DTT), derived from diffusion tensor imaging (DTI), allows three-dimensional visualization and estimation of the cingulum (Malykhin et al., 2008). Many DTI studies have reported on injury of the cingulum following traumatic brain injury (TBI) (Hong and Jang, 2010; Hong et al., 2012; Jang et al., 2013). However, very little is known about neural recovery of injured cingulums following TBI. In the current study, we presented with a patient that had TBI and appeared to show neural recovery of injured cingulums on DTT. A 19-year-old, right-handed female who had suffered a traffic accident underwent conservative management for diffuse traumatic axonal injury at the department of neurosurgery of a university hospital. The patient lost consciousness for 5 days due to head trauma since the time of TBI onset and transferred to the rehabilitation department of the same hospital. Brain MRI was performed 2 weeks after onset and showed subdural hygroma on both frontotemporal areas and an encephalomalactic lesion at the body of the corpus callosum (Figure 1A). Upon evaluation for cognitive function performed 2 weeks after onset, the patient revealed severe cognitive impairment (total intelligence quotient (IQ) on the Wechsler adult intelligence scale: 65, global memory on the Memory Assessment Scale (MAS): 61(< 1%ile), immediate memory on MAS: 83 (13%ile). The patient underwent comprehensive rehabilitation, including physical and cognitive therapies, until 6 months after onset and showed nearly complete recovery in terms of motor and language functions. At the 6-month evaluation, the cognitive impairment improved as much as total IQ: 82, global memory on the MAS: 102 (55%ile), immediate memory on MAS: 107 (68%ile) (Wechsler, 1981; Williams, 1991). Figure 1 Conventional MRI and diffusion tensor tractography (DTT) images of a 19-year-old female patient with traumatic brain injury. DTIs were acquired twice (2 weeks and 6 months after onset) using a 6-channel head coil on a 1.5-T Philips Gyroscan Intera (Philips, Ltd., Best, The Netherlands) with single-shot echo-planar imaging. In addition, one age-matched normal subject (a 21-year-old female) was enrolled in this study. Imaging was performed. For each of the 32 non-collinear diffusion-sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissure-posterior commissure line. Imaging parameters used were as follows: acquisition matrix = 96 × 96, reconstructed to matrix = 128 × 128 matrix, field of view = 221 × 221 mm2, repetition time = 10,726 ms, echo time = 76 ms, sensitivity encoding factor = 2, echo planar imaging factor = 49 and b = 1,000 s/mm2, number of excitations = 1, and a slice thickness of 2.3 mm. Fiber tracking was performed using the fiber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software (Mori et al., 1999; Stieltjes et al., 2001). The cingulums were reconstructed using fibers passing through two regions of interest (ROIs). The first ROI was drawn at the middle portion of cingulum (green color) on the color map with coronal image (blue color: superioinferior orientation; red color: mediolateral orientation; green color: anteroposterior orientation) (Malykhin et al., 2008). The second ROI was drawn at the posterior portion of cingulum (green color) on the color map with coronal image (Malykhin et al., 2008). Termination criteria were fractional anisotropy (FA) 25°. On 2-week DTTs for cingulums in the patient, we observed discontinuations of both cingulums anterior to the genu of corpus callosum. However, on 6-month follow up DTTs, the left cingulum was elongated and showed the integrity to the left basal forebrain and the right cingulum was connected to left basal forebrain by a new tract that passed anterior to the genu of corpus callosum and was not observed on 2-week DTT (Figure 1B). In the current study, we observed changes of DTT for cingulum along with changes of cognitive impairment in a patient with TBI. Two-week DTTs of the patient showed discontinuations above the basal forebrain anterior to the genu of corpus callosum in both cingulums. Considering that the patient satisfied the diagnostic criteria of diffuse axonal injury (a mechanism of injury associated with significant acceleration/deceleration force, loss of consciousness for 5 days since the onset of TBI without a lucid interval, no specific lesions in the basal forebrain and cingulum areas), the patient appeared to get traumatic axonal injury in the anterior portion of both cingulums by the traffic accident. However, on 6-month follow up DTTs, the left cingulum was elongated to the basal forebrain and the right cingulum was connected to the left basal forebrain via a new tract that passed anterior to the genu of corpus callosum. These DTT changes of both cingulums appeared to indicate the recovery of both injured cingulums and to coincide with the improvement of cognitive impairment, in particular, the improvement of immediate memory impairment (Wolk and Budson, 2010). In conclusion, we report on a patient who appeared to show recovery of injured cingulums following TBI. Regarding the recovery of an injured cingulum, to the best of our knowledge, there was only a patent with hypoxic ischemic brain injury following spontaneous subarachnoid hemorrhage whose discontinued cingulum was elongated to the basal forebrain (Seo and Jang, 2013). Therefore, this is the first DTT study that tried to demonstrate the recovery of injured cingulum in patients with TBI. We believe that the evaluation of cingulum using DTT would be helpful in the diagnosis of cingulum injury and in estimating the changes of cingulum injuries in TBI. However, because it is a case report, this study is limited. Further complementary studies involving larger numbers of patients are warranted. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, No. 2012R1A1A4A01001873.

Prior to development of diffusion tensor imaging (DTI), there were many difficulties in visualization and estimation of the Papez circuit in the live human brain (Papez, 1995). Diffusion tensor tractography (DTT), derived from DTI, allows for identification and visualization of neural tracts in the Papez circuit (Concha et al., 2005; Kwon et al., 2010; Granziera et al., 2011; Jang and Yeo, 2013; Jang et al., 2014a). In the current study, using DTT, we report on a patient who showed injured thalamocortical tract between the anterior thalamic nuclei and the cingulate gyrus following a putaminal hemorrhage. A 55-year-old male patient received conservative management for a putaminal hemorrhage in the left hemisphere (Figure 1A). He showed cognitive dysfunction since the onset of putaminal hemorrhage. Results of evaluation at 5 weeks after onset using the Memory Assessment Scale (MAS) which is a comprehensive standardized memory assessment battery that consists of four memory subsets: global memory, short-term memory, verbal memory, and visual memory indicate severe memory impairment (global memory: 71 (3%ile), short term memory: 75 (5%ile), verbal memory: 64 (1%ile), and visual memory: 94 (35%ile)) although Wechsler Adult Intelligence Scale (IQ) was within normal range as 94 (Williams, 1991). Figure 1 Brain CT, T2-weighted MR images, and diffusion tensor tractography (DTT) images of a 55-year-old male patient with a putaminal hemorrhage in the left hemisphere exhibiting cognitive dysfunction. DTI data was acquired at 5 weeks after onset using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Ltd., Best, the Netherlands) with single-shot echo-planar imaging. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 70 contiguous slices parallel to the anterior commissure-posterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed to matrix = 192 × 192; field of view = 240 × 240 mm2; repetition time (TR) = 10,398 ms; echo time (TE) = 72 ms; parallel imaging reduction factor (SENSE factor) = 2; echo planar imaging factor = 59; b = 1,000 s/mm2; and a slice thickness of 2.5 mm. Fiber tracking was performed using a probabilistic tractography method based, and applied in the present study utilizing tractography routines implemented in Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL; www.fmrib.ox.ac.uk/fsl). Each neural tract of the Papez circuit was determined by selection of fibers passing through seed and target regions of interest (ROIs) (Concha et al., 2005; Kwon et al., 2010; Jang and Yeo, 2013). We manually drew the ROIs as follows: thalamocortical tract: seed ROI – the cingulate gyrus, first target ROI – anterior limb of internal capsule, second target ROI – anterior thalamic nuclei; fornix: seed ROI – mammillary body, target ROI – crus of fornix; mammillothalamic tract: seed ROI – anterior thalamic nucleus, first target ROI – portion of isolated mammillothalamic tract, second target ROI – mammillary body; cingulum: seed ROI – middle portion of the cingulum, target ROI – posterior portion of the cingulum. Out of 5,000 samples generated from a seed voxel, results were visualized at the threshold of 5 streamline through each voxel for analysis. In the right hemisphere, the whole Papez circuit including the thalamocortical tract, cingulum, fornix, and mammillothalamic tract were reconstructed. By contrast, the thalamocortical tract was not reconstructed in the left hemisphere due to the putaminal hemorrhage. The Papez circuit, described by James Papez in 1937, is known to play important roles in control of emotion and memory (Papez, 1995). The pathway of the Papez circuit was reported as follows: hippocampal formation – fornix – mammillary bodies – anterior thalamic nuclei – cingulate gyrus – cingulum – parahippocampal gyrus – hippocampus (Papez, 1995). Previous studies using DTT have reported on injury of a portion of the Papez circuit including fornix, mammillothalamic tract and cingulum (Wang et al., 2008; Yeo and Jang, 2013; Jang et al., 2014a, b; Kwon et al., 2014). Regarding the thalamocortical tract between anterior thalamic nuclei and cingulate gyrus, a recent study reported on a patient who showed thinned thalamocortical tract and non-reconstruction of the mammillothalamic tract following anterior thalamic infarction (Jang et al., 2014a). In the current study, we investigated DTT findings of the neural tracts of the Papez circuit and found injury of the left thalamocortical tract between anterior thalamic nuclei and cingulate gyrus. We think that this patient's memory impairment was mainly the result of the injury of this tract in the Papez circuit. To the best of our knowledge, this is the first study to demonstrate neural tract injuries of the Papez circuit following an intracerebral hemorrhage. We think that further studies involving larger numbers of patients and recovery of memory function using follow up DTT are necessary. This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, No. 2012R1A1A4A01001873.

The fornix, a part of the Papez circuit, transfers information of episodic memory between the medial temporal lobe and the medial diencephalon (Aggleton and Brown, 1999). The right medial temporal lobe is known to be specialized for visual memory and the left medial temporal lobe for verbal memory (Tucker et al., 1988; Aggleton and Brown, 1999). Many studies have reported on fornix injury, however, most of them focused on bilateral injury (Tucker et al., 1988; Aggleton et al., 2000; Nakayama et al., 2006; Sugiyama et al., 2007; Tsivilis et al., 2008; Wang et al., 2008; Jang et al., 2009; Chang et al., 2010; Hong and Jang, 2010; Yeo et al., 2011). To the best of our knowledge, three studies have reported on injury of the unilateral fornical crus (Tucker et al., 1988; Hong and Jang, 2010; Yeo et al., 2011). Among these studies, Tucker et al. (1988) reported on a patient who showed severe verbal memory impairment after unilateral transaction of the left fornical crus during surgery for removal of astrocytoma. Hong and Jang (2010) reported on a patient who showed selective verbal memory impairment due to left fornical crus injury, which was ascribed to diffuse axonal injury following head trauma. Subsequently, Yeo et al. (2011), who investigated the effect of intraventricular hemorrhage on white matter in 10 patients with intraventricular hemorrhage, reported on one patient with left fornical crus injury and nine patients with fornical body injury without clinical data on memory impairment, except for the Mini-Mental State Examination (MMSE). To the best of our knowledge, this is the first study which demonstrates selective verbal memory impairment due to left fornical crus injury following spontaneous intraventricular hemorrhage. It is difficult to precisely assess the fornix due to its long, thin appearance and its location within the brain. In addition, discrimination of the whole fornix from adjacent neural structure using conventional brain CT or MRI is impossible. By contrast, diffusion tensor tractography (DTT), which is derived from diffusion tensor imaging (DTI), has enabled three-dimensional visualization of the fornix, and many studies have reported on fornix injury using DTT (Nakayama et al., 2006; Sugiyama et al., 2007; Wang et al., 2008; Jang et al., 2009; Chang et al., 2010; Hong and Jang, 2010; Yeo et al., 2011). In the current study, using DTT, we report on a patient who showed selective verbal memory impairment due to left fornical crus injury following intraventricular hemorrhage. A 33-year-old, right-handed male underwent conservative management for spontaneous intraventricular hemorrhage in the left lateral ventricle at the department of neurosurgery in a university hospital. Brain CT at onset showed that the hematoma was mainly located on the lateral side of the left fornix (Figure 1A). One month after onset, he was transferred to the rehabilitation department of a university hospital in order to undergo rehabilitation. Cognitive function was evaluated twice (1 month and 4 months after onset) using two scales: the MMSE and the MAS (Folstein et al., 1975; Wechsler D, 1991). The MMSE (full score 30, cut-off score , visual memory: 77; 6%ile, and verbal memory: 53; 1%ile >); in contrast, at 4 months after onset, the patient showed marked improvement of visual memory with selective impairment of verbal memory (global memory: 70; 2%ile, visual memory: 108; 70%ile, and verbal memory: 56; 1%ile >). Figure 1 Brain CT and diffusion tensor tractography (DTT) images of a 33-year-old male patient with injury of the left fornical crus following intraventricular hemorrhage. DTTs were acquired twice (1 month and 4 months after onset) using a 1.5-T Philips Gyroscan Intera system (Philips, Ltd, Best, the Netherlands) equipped with a Synergy-L Sensitivity Encoding (SENSE) head coil using a single-shot, spin-echo planar imaging pulse sequence. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 60 contiguous slices parallel to the anterior commissure-posterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96, reconstructed to matrix = 192 × 192 matrix, field of view = 240 mm × 240 mm, repetition time = 10,398 ms, echo time = 72 ms, parallel imaging reduction factor (SENSE factor) = 2, echo planar imaging factor = 59 and b = 1,000 s/mm2, number of excitations = 1, slice gap = 0 mm and thickness = 2.5 mm. Eddy current-induced image distortions were removed using affine multi-scale two-dimensional registration at the Oxford Centre for Functional Magnetic Resonance Imaging of Brain (FMRIB) Software Library (FSL; www.fmrib.ox.ac.uk/fsl). DTI-Studio software (CMRM, Johns Hopkins Medical Institute, Baltimore, MD, USA) was used for evaluation of the fornix. For analysis of the fornix, the seed region of interest (ROI) was drawn at the junction between the body and column of each fornix on a coronal image with the color map. Target ROIs were placed on the crus of the right and left fornix on a coronal image with the color map. Fiber tracking was started at any seed voxel with a fractional anisotropy (FA) > 0.2 and ended at a voxel with a fiber assignment of < 0.2 and a tract turning angle of < 70 degrees. One-month DTT for the fornix showed a discontinuation of the left fornical crus, which was not observed in four male age- and sex-matched right handed normal control subjects (mean age 33.25 years (range 29–39 years)) and the discontinued left fornical crus was degenerated toward the fornical body as shown on 4-month DTT (Figure 1B). By contrast, the left fornical column was extended to the left medial temporal lobe on both 1- and 4-month DTTs. In the current study, we reported on a patient who showed selective verbal memory impairment due to left fornical crus injury on DTT. The patient showed left fornical crus injury on both 1- and 4-month DTTs. We evaluated the patient's cognitive function using two neuropsychological tests: the MMSE and the MAS. The MMSE is a screening test for general cognitive function by evaluating the subject's orientation, memory, attention, calculation, visuospatial, and language abilities (Folstein et al., 1975). The MAS is a comprehensive standardized memory assessment test that yields scores for four factors: total memory, short-term memory, verbal memory, and visual memory (Williams, 1991). The patient's general cognitive function was within normal range with a full MMSE score of 30 at both 1 and 4 months after onset. However, the patient showed impairment in both visual and verbal memory at 1 month after onset (more severe impairment in verbal memory); in contrast, at 4 months after onset, the patient showed selective verbal memory impairment with marked improvement of visual memory. Because the left medial temporal lobe is known to be specialized for verbal memory, so the patient's selective verbal memory impairment was ascribed to the left fornical crus injury (Tucker et al., 1988; Aggleton et al., 1999). The extension of the left fornical column to the left medial temporal lobe appears to be attributed to neural reorganization following injury of the left fornical crus (Yeo and Jang, 2013). The hematoma in the present case was mainly located on the lateral side of the left fornix. Several studies have reported that periventricular neural tissue could be injured by intraventricular hemorrhage through mechanical or chemical mechanisms: (1) mechanical: following intraventricular hemorrhage, the increased intracranial pressure or direct mass effect can reduce cerebral perfusion pressure and cause secondary ischemic injury to periventricular white matter. (2) Chemical: a blood clot itself can cause extensive damage to the ependymal layer, subependymal layer, or periventricular tissues by release of potentially damaging substances, such as free iron, which may generate free radicals or inflammatory cytokines (Wasserman and Schlichter, 2008; Chua et al., 2009; Dai et al., 2009; Yeo et al., 2011). Therefore, we presumed that the left fornix crus was injured by the hematoma, although we could not determine whether the injury could be ascribed to a mechanical or chemical pathophysiological mechanism. In conclusion, we report on a patient who showed selective verbal memory impairment due to injury of the left fornical crus following intraventricular hemorrhage. This study is limited to a single case report. Further studies involving a larger number of patients are required.

Motor weakness is one of the most serious disabling sequelae of stroke. For successful rehabilitation, thorough estimation of the state of injured neural tracts for motor function is mandatory. After development of diffusion tensor tractography (DTT), which is derived from diffusion tensor imaging (DTI), three-dimensional reconstruction and estimation for three motor tracts, such as the corticospinal tract, the rubrospinal tract, and the corticoreticular pathway became possible (Kunimatsu et al., 2004; Puig et al., 2010; Yang et al., 2011). The corticospinal tract is known to be a major neural tract for motor function in the human brain (Binkofski et al., 1996). Many studies using DTI have reported on recovery of an injured corticospinal tract in various brain pathologies, including cerebral infarct, intracerebral hemorrhage, and traumatic diffuse axonal injury (Skoglund et al., 2008; Jang, 2011a). Brain herniation occurs when the brain shifts across structures such as the falx cerebri or the tentorium cerebelli within the skull (Johnson et al., 2002). Brain herniation usually accompanies severe neurological sequelae, therefore, accurate evaluation of the state of an injured neural tract in patients with brain herniation is necessary to elucidate the causes of neurological manifestations, and for establishment of scientific rehabilitative strategies, and in prediction of prognosis (Johnson et al., 2002; Yoo et al., 2008; Cho et al., 2011; Hong et al., 2012). Several studies have reported on injury of the corticospinal tract by transtentorial herniation (Yoo et al., 2008; Cho et al., 2011; Choi et al., 2012; Hong et al., 2012). In addition, some studies have demonstrated recovery of a corticospinal tract injured by transtentorial herniation (Kwon et al., 2011; Yeo and Jang, 2013). However, very little is known about injury and recovery of the corticospinal tract related to subfalcine herniation. In the current study, we report on a patient who showed recovery of the corticospinal tract, which was injured by the effect of a subfalcine herniation, using DTT. A 53-year-old, right-handed male presented with mental deterioration and quadriparasis, which occurred at the onset of subdural hematoma in the right fronto-parietal-temporal lobe and intracerebral hemorrhage in the right occipital lobe (Figure 1A). Brain CT images showed midline shifting under the falx cerebri toward the left hemisphere. He underwent decompressive craniectomy and removal of a hematoma at the department of neurosurgery of a university hospital. At 6 weeks after onset, he was transferred to the rehabilitation department of the same university hospital for rehabilitation. Figure 1 Brain CT, T2-weighted MRI, and diffusion tensor tractography images of a 53-year-old male patient with subdural hematoma in the right fronto-parietal-temporal lobe and intracerebral hemorrhage in the right occipital lobe exhibiting mental deterioration ... The Motricity Index (MI) and Medical Research Council (MRC) were used for evaluation of motor function of the affected extremities. The reliability and validity of the MI is well-established (maximum score: 100). He presented with quadriparesis of all four extremities at onset (MI: 0/0) and at the start of rehabilitation (6 weeks after onset, [MI]: 55/55) (Table 1). From 6 to 12 weeks after onset, he received comprehensive rehabilitative management, including administration of neurotrophic drugs (ropinirole, levodopa, and amantadine), movement therapy, and neuromuscular electrical stimulation of the affected finger extensors and ankle dorsiflexors (Scheidtmann et al., 2001). Movement therapy focused on improvement of motor weakness and was performed at the physical and occupational therapy sessions five times per week. His quadriparesis was improved from the MI score of 55/55 points at 6 weeks to 79/75 points (12 weeks) during a 6-week period of rehabilitation. After discharge, he was prescribed the same medication and performed a home exercise program, which focused on walking and upper extremity mobility. As a result, his weakness was recovered to a nearly normal state at 7 months after onset (96/96 points). The patient provided signed, informed consent and our institutional review board approved the study protocol. Table 1 Changes in motor function of the patient DTI data were acquired twice (6 weeks and 7 months after onset) using a six-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Ltd., Best, the Netherlands) with single-shot echo-planar imaging. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 70 contiguous slices parallel to the anterior commissure-posterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96, reconstructed to matrix = 192 × 192 matrix, field of view = 240 × 240 mm2, repetition time = 10,398 ms, echo time = 72 ms, parallel imaging reduction factor (SENSE factor) = 2, echo planar imaging factor = 59 and b = 1,000 s/mm2, number of excitations = 1, slice gap = 0, and a slice thickness of 2.5 mm. Fiber tracking was performed using the fiber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software. Each of the DTI replications was intra-registered to the baseline “b0” images to correct for residual eddy-current image distortions and head motion effect, using a diffusion registration package (Philips Medical Systems). Corticospinal tracts were determined by selection of fibers passing through two regions of interest (ROIs) at the upper and lower pons (portion of anterior blue color) (Jang, 2011b). Fiber tracking was performed with a fractional anisotropy (FA) threshold of > 0.15 and a direction threshold of < 27°. Both corticospinal tracts originated from the cerebral cortex, including the primary motor cortex, which passed along the known corticospinal tract pathway (Figure 1C). However, both corticospinal tracts were narrowed from the cerebral cortex to the subcorical white matter (right: between the cerebral cortex and the subcortical white matter just below the cerebral cortex, left: between the cerebral cortex and the subcortical white matter at the level of the corpus callosum). However, thickenings of these narrow portions were observed on 7-month DTT. The subfalcine herniation occurs when one hemisphere swells and shifts the cingulate gyrus beneath the falx cerebri, consequently causing injury of the cingulate gyrus (Johnson et al., 2002). In the current study, on 6-week DTT, we found that both corticospinal tracts were narrowed at the subcortical white matter in both hemispheres, suggesting injury of the corticospinal tract. Because the subfalcine herniation indicates injury of the cingulate gyrus by herniation below the falx cerebri, it appears that the right corticospinal tract was injured mainly by compression of the right subdural hematoma and the left corticospinal tract was injured by the effect of the subfalcine herniation. The quadriparesis of the patient was compatible with the corticospinal tract findings on 6-week DTT. Thickenings of narrowed portions of both corticospinal tracts on 7-month DTT appear to indicate recovery of the injured corticospinal tracts. The good recovery of quadriparesis in this patient appears to coincide with changes of the injured corticospinal tracts in both hemispheres. Since the introduction of DTI, many studies using DTI have reported on injury of the corticospinal tract by transtentorial herniation in patients with brain injury (Yoo et al., 2008; Cho et al., 2011; Choi et al., 2012; Hong et al., 2012). As for recovery of the corticospinal tract injured by brain herniation, two studies have reported on recovery of a corticospinal tract injured by transtentorial herniation in patients with intracerebral hemorrhage and traumatic brain injury, respectively (Kwon et al., 2011; Yeo and Jang, 2013). With regard to the subfalcine herniation, Hong et al. (2012) reported on injury of the cingulum and fornix in two patients with traumatic brain injury. As a result, to the best of our knowledge, this is the first study to demonstrate injury and recovery of the corticospinal tract related to a subfalcine herniation. In conclusion, we described a patient who showed recovery of the corticospinal tracts in both hemispheres, which appeared to be injured by the effect of a subfalcine herniation. This study demonstrated injury of the corticospinal tract and the process of recovery of an injured corticospinal tract in a patient with a subfalcine herniation, using DTT. Therefore, we believe that DTT would be useful in detection of an injury of a neural tract and in demonstration of recovery of an injured corticospinal tract in patients with a subfalcine herniation. However, further studies involving large numbers of patients need to be performed.

Idiopathic Parkinson's disease (IPD) is a progressive, neurodegenerative movement disorder characterized by bradykinesia, muscular rigidity, postural instability and tremor. IPD is usually diagnosed based on clinical findings, but diagnoses are only 75–90% accurate when compared with autopsy results. Improving diagnostic accuracy is critical for the early differentiation of IPD from other Parkinsonism-related disorders because of differences in their prognoses and treatment. Furthermore, IPD is clinically heterogeneous, with variable prognosis. Although the biological function of neuromelanin has not yet been determined, the selective vulnerability of neuromelanin-containing neurons in patients with IPD suggests a role for this pigment in neurodegeneration. Recently developed ultra-high-field magnetic resonance imaging (MRI) systems produce T1-weighted neuromelanin-sensitive images with very high spatial resolution, enabling the depiction of tissue containing neuromelanin. Here we review recent advances in neuromelanin-sensitive MRI in IPD and related conditions suggesting that neuromelanin may be a potential diagnostic biomarker for IPD. Neuromelanin is a dark polymer produced in specific populations of catecholaminergic neurons in the brain. Three main regions of the brain contain neuromelanin-producing cells: the substantia nigra (SN) of the midbrain, the locus coeruleus (LC) within the pons and the ventrolateral reticular formation and nucleus of the solitary tract in the medulla oblongata. Moreover, two of these regions, the SN and the LC, contain large clusters of pigmented neurons that appear macroscopically as darkened areas (Fedorow et al., 2005). Parkinsonian syndrome is a heterogeneous group of movement disorders, which can be subdivided into IPD, genetic forms of Parkinson's disease (PD) and atypical parkinsonian syndrome. In addition, several other neurodegenerative disorders may show clinical signs of parkinsonism. The etiology, histopathology, clinical manifestation and disease course of these disorders vary significantly. The loss of neuromelanin-containing cells within the SN and LC is a primary pathological diagnostic criterion for IPD. The presence of neuromelanin in these vulnerable cells suggests a role for this pigment in the neurodegenerative process of IPD. The amount of neuromelanin contained within the dopaminergic neurons of the midbrain has been reported to be inversely related to the relative vulnerability of these cells to IPD (Hirsch et al., 1988). In addition to the degree of neuromelanin pigmentation, the position of neuromelanin-containing cells within the nigral complex was also found to be a key factor for neuronal survival in IPD (Damier et al., 1999). Neuromelanin has a high chelating ability for iron, and has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration, such as pesticides and MPP +, suggesting a neuroprotective role of neuromelanin (Zecca et al., 2001). Cell death observed in IPD may be partly due to oxidative stress. This oxidation may also be relieved by neuromelanin. Following its binding of iron, neuromelanin acts as a paramagnetic agent. Recently developed ultra-high-field magnetic resonance imaging (MRI) systems produce T1-weighted neuromelanin-sensitive images of very high spatial resolution (Enochs et al., 1997; Sasaki et al., 2006; Bolding et al., 2013). On these images, neuromelanin-containing tissues appear as foci of high signal intensity, with the intensity proportional to the neuromelanin concentration. Neuromelanin-sensitive MRI can be used to directly measure the volume or concentration of neuromelanin in the SN and LC, suggesting that this modality may be able to distinguish IPD from other related conditions. We review here the usefulness of neuromelanin MRI for the diagnosis of parkinsonian syndrome, with special reference to neuropathological findings.

Optic radiation (OR) injury can occur following various brain injuries and it is usually accompanied by visual field defects (Zhang et al., 2006). OR is very important for performing activities of daily living and providing safety. However, the OR cannot be clearly demarcated from adjacent neural structures and thereby conventional brain MRI has limited specificity in diagnosis of OR injury. Diffusion tensor tractography (DTT), which is derived from diffusion tensor imaging (DTI), has enabled three-dimensional reconstruction of the OR. Many DTT studies have reported OR injury following various brain injuries (Shinoura et al., 2010; Lee et al., 2012; Seo et al., 2013; Jang and Seo, 2015), however, few DTT studies on OR injury have been reported. In this study, we reported DTT findings of OR injury in one 58-year-old male patient. The patient was diagnosed with spontaneous subarachnoid hemorrhage, intraventricular hemorrhage (IVH), and intracerebral hemorrhage (ICH) in the left subcortical white matter, and underwent endovascular embolization and right frontal extraventricular drainage for ruptured arteriovenous malformation at the department of neurosurgery of a local hospital (Figure 1A). He complained of a right homonymous visual field defect and mild right hemiparesis since the onset, and visited a university hospital for precise evaluation at 12 months after onset. Brain MRI showed a leukomalactic lesion in the left subcortical white matter below the posterior limb of the internal capsule: however, no specific lesion was observed on the occipital lobe. Right bilateral homonymous hemianopsia was detected in Humphrey Visual Field (HVF) test (Figure 1C). Figure 1 Results of CT, MRI, diffusion tensor tractography (DTT), and Humphrey visual field test in a 58-year-old male patient with intraventricular hemorrhage. After providing signed informed consent, the patient was included in this study under the approval by Institutional Review Board of Yeungnam University, Republic of Korea. DTI data were acquired at 12 months after onset using a 1.5-T Philips Gyroscan Intera system (Philips, Ltd, Best, the Netherlands) equipped with a synergy-L Sensitivity Encoding (SENSE) head coil utilizing a single-shot, spin-echo planar imaging pulse sequence. For each of the 32 noncollinear and noncoplanar diffusion sensitizing gradients, 67 contiguous slices were acquired parallel to the anterior commissure-posterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed matrix = 192 × 192; field of view = 240 × 240 mm2; repetition time/echo time = 10,398/72 ms; SENSE factor = 2; EPI factor = 59, b = 1,000 s/mm2, NEX = 1, slice thickness = 2.5 mm. Fiber tracking was performed using the fiber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software (Philips Extended MR WorkSpace 2.6.3; Philips, Ltd, Best, the Netherlands). Each of the DTI replications was intra-registered to the baseline “b0” images in order to correct for residual eddy-current image distortions and head motion effect, using a diffusion registration package (Philips Medical Systems) (threshold fractional anisotropy = 0.15, angle = 27). ORs were ascertained by selection of fibers passing through ROIs. The seed ROI was placed on the lateral geniculate nucleus (LGN) on the color map, and the target ROI was placed on the bundle of the OR at the middle portion between LGN and occipital pole (Hofer et al., 2010; Jang and Seo, 2015). The right OR was reconstructed from the LGN to the primary visual cortex, while the left OR showed a discontinuation at the middle portion around the temporal horn of the lateral ventricle. Green color density of the left OR was largely decreased around the middle portion of the left OR (Figure 1B). We reported on a patient who showed a left OR injury on DTT following SAH, IVH, and ICH, which was not detected by conventional brain MRI. This evidence of the left OR injury on DTT coincided well with the right bilateral homonymous hemianopsia on the visual field test. According to the previous studies, all types of hemorrhages (SAH, IVH, and ICH) in this patient could cause neural injury (Chua et al., 2009; Yeo et al., 2011; Seo et al., 2013; Jang and Kim, 2015; Jang and Yeo, 2015). However, considering the anatomical locations of hemorrhages within the OR, the ICH around the LGB appeared to be the most plausible cause of the left OR injury. However, DTT showed discontinuation of the left OR in the middle portion around the temporal horn of the lateral ventricle, indicating an injury of the left OR by the hemorrhage in the lateral ventricle. Previous studies have suggested that injury to periventricular white matter by IVH could occur through mechanical (increased intracranial pressure or direct mass) or chemical mechanisms (a blood clot itself can cause extensive damage) (Chua et al., 2009; Yeo et al., 2011; Jang and Yeo, 2015). In this study, considering that the middle portion of the left OR is close to the temporal horn of the lateral ventricle, and the middle portion of the left OR appeared to be affected by hematoma in this ventricle. In conclusion, we report on a patient who had a left OR injury detected by DTT. Our results suggest that DTT is a useful technique for detection of the OR injury not detected on conventional brain MRI. Therefore, we think that DTT for the OR should be recommended for more precise evaluation along with conventional brain MRI for patients who complain of visual field defect following brain injury. To the best of our knowledge, this is the first study to demonstrate OR injury following SAH, IVH, and ICH. However, this study is limited because it is a case report. Further complementary studies involving larger numbers of patients are warranted. This work was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (MSIP), No. 2015R1A2A2A01004073.

Hydrocephalus can induce secondary parkinsonism (Shahar et al., 1988; Aggarwal et al., 1997; Racette et al., 2004). Physical factors such as increased ventricular pressure near the upper midbrain and basal ganglia are thought to cause mechanical disruption of dopaminergic systems (i.e., the nigrostriatal pathways from the medial substantia nigra to the caudate nuclei and putamen and its frontal projection fibers from the basal ganglia) (Asamoto et al., 1998; Yomo et al., 2006). Symptoms of parkinsonism are bradykinesia with rigidity, resting tremor, or postural instability, which can deteriorate a patient's physical function and functional recovery (Racette et al., 2004). Parkinsonian symptoms can be controlled by dopaminergic medication, meaning that the accurate diagnosis of secondary parkinsonism is important for proper management of stroke patients (Shahar et al., 1988; Aggarwal et al., 1997; Racette et al., 2004). Previous studies have investigated dopaminergic system dysfunction induced by hydrocephalus using single photon emission computed tomography (SPECT) and position emission tomography (PET) scanning (Shahar et al., 1988; Aggarwal et al., 1997; Racette et al., 2004; Nakayama et al., 2007). However, these methods are limited in their ability to clearly present the dopaminergic system.

The fornix, which is involved in transfer of episodic memory, is an important structure of the Papez circuit between the medial diencephalon and the medial temporal lobe. Many studies using DTI have reported on injury of the fornix in patients with brain injury (Nakayama et al., 2006; Sugiyama et al., 2007; Wang et al., 2008; Chang et al., 2010). However, only a few studies on recovery of an injured fornix in patients with brain injury, including traumatic brain injury and stroke, have been reported (Yeo et al., 2011; Yeo and Jang, 2013a, b). In this study, using follow up DTT images, we reported on a patient who showed recovery of injured fornical crura following a neurosurgical operation for a brain tumor. A 48-year-old female patient underwent craniotomy and a navigator assisted removal of craniopharyngioma at the university hospital. Brain MRIs showed a cystic mass at the suprasellar space before the operation, and a lesion and hematoma in the body of the corpus callosum and the lateral ventricle 1 day after the operation (Figure 1A). According to pathology, the patient was diagnosed suffering from a craniopharyangioma. The patient had shown severe memory impairment since the operation and underwent neuropsychological evaluations at 6 weeks after onset: Memory Assessment Scale [MAS, global memory: 58 ( 1%ile), short term memory: 101 (53%ile), verbal memory: 67 (1%ile), and visual memory: 70 (2%ile)], MMSE: 24. Figure 1 Brain magnetic resonance and diffusion tensor tractography (DTT) images of the fornical crura in a patient with a brain tumor after neurosurgical operation. DTI was performed three times (2, 6 and 20 months after onset) using a 6-channel head coil on a 1.5T Philips Gyroscan Intera. Fiber tracking was based on the fiber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software. For reconstruction of the fornix, the first region of interest (ROI) was placed at the junction between the body and column of the fornix on a coronal image of the color map. The second ROIs were placed on each side of the crus of the fornix on a coronal image of the color map, respectively (Yeo and Jang, 2013b). On 2-month DTT images, discontinuations were observed in both fornical crura (Figure 1B). A collateral branch from the end of the right fornical body was observed, which ended in the right temporal lobe via the splenium of the corpus callosum. On 6-month DTT images, fornical crura emerged from the end of the fornical body on both sides; in contrast, the right collateral branch was shortened and a collateral branch emerged from the left fornical body. On 20-month DTT images, the fornical crura were elongated to the medial temporal lobe on both sides and the collateral branches had disappeared on both sides. In the current study, we investigated changes in DTT findings of injured fornical crura following a neurosurgical operation in a patient with a brain tumor. After removal of the tumor, a lesion and hematoma were observed in the body of the corpus callosum and the lateral ventricle. We observed discontinuations of the bilateral fornix crura on 2-month DTT images. Based on previous studies demonstrating the vulnerability of the fornix to intraventricular hemorrhage and lesion in the corpus callosum, the fornix injury in this patient was ascribed to the intraventricular hemorrhage and neurosurgical operation through the body of the corpus callosum (Chang et al., 2010; Yeo et al., 2011). We observed two kinds of changes of injured fornical crura on three follow up DTT images: 1) recovery of discontinued fornical crura on both sides, consequently, the ends of injured fornical crura were connected to the medial temporal lobe on both sides on 20-month DTT images, and 2) the collateral branches via the splenium of the corpus callosum from the injured fornical body disappeared with the recovery of injured fornical crura. Previous studies have reported that collateral branches via the splenium of the corpus callosum result from development of compensatory neural tracts following injury of the fornical crus (Yeo and Jang, 2013a, b; Lee et al., 2014). Therefore, we believe that the compensatory collateral branches via the corpus callosum had disappeared along with the recovery of the injured fornical crura. The improvement of impaired memory in the visual and verbal observed in this patient for 20 months may be additional evidence of the recovery of injured fornical crura in this patient. Since introduction of DTI, a few studies have reported on the recovery of an injured fornix in patients with brain injury (Yeo and Jang, 2013a, b; Lee et al., 2014). In 2013, Yeo and Jang (2013b) reported on a patient who showed compensatory neural tracts (an abnormal neural tract originating from an injured fornical crus passed through the splenium of the corpus callosum to connect to the medial temporal lobe and another abnormal neural tract originating from the fornical column was connected to the medial temporal lobe) after head trauma resulting in bilateral injury of the fornical crura. Yeo and Jang (2013a) also reported on a patient who underwent coiling for a ruptured anterior communicating cerebral artery aneurysm and conservative management for subarachnoid and intraventricular haemorrahage. They showed that the end of the discontinued fornical body was connected to the splenium of the corpus callosum and then branched to the medial temporal lobe and thalamus. Lee and Jang (2014) recently reported on the change of an injured fornix in a patient with traumatic axonal injury. One branch from the injured fornical body was connected to the medial temporal lobe via the splenium of the corpus callosum, and two branches from both fornical columns were connected to the medial temporal lobes respectively. As a result, to the best of our knowledge, this is the first study to demonstrate the recovery of injured fornical crura in a patient with brain injury. However, limitation of DTI should be considered (Yamada et al., 2009). DTI may underestimate or overestimate the fiber tracts. In addition, fiber complexity and crossing can prevent full reflection of the underlying fiber architecture by DTI (Yamada et al., 2009). In conclusion, we reported on a patient who showed recovery of injured fornical crura following a neurosurgical operation for a brain tumor. This finding appears to suggest a mechanism for recovery of injured fornical crura. Because it is based on a single case report, this study is limited. Larger-scale complementary studies needed to be conducted. This work was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (MSIP), No. 2015R1A2A2A01004073.

Aging is the accumulation of multidimensional deterioration of processing of biological, psychological, and social changes with expansion over time (Bowen and Atwood, 2004; Grady, 2012). Aging-related changes are typically accompanied by decline in cognitive function, urinary control, sensory-motor function, and gait ability (Bradley et al., 1991; Bowen and Atwood, 2004; Hedden and Gabrieli, 2004; Grady, 2012; Moran et al., 2012). In addition, a number of studies have suggested changes in brain structure with normal aging, such as decrease in cortical thickness or increase in ventricular width (Blatter et al., 1995; Tang et al., 1997; Uylings and de Brabander, 2002; Preul et al., 2006; Apostolova et al., 2012). In particular, ventricular enlargement has been suggested as a structural biomarker for normal aging and progression of some illnesses, such as Alzheimer's disease (Blatter et al., 1995; Tang et al., 1997; Uylings and de Brabander, 2002; Preul et al., 2006; Apostolova et al., 2012). However, the question of how this structural change in the brain in normal elderly affects change of white matters remains a topic of interest and concern. Diffusion tensor imaging allows for evaluation of white matter due to its ability to capture and quantify water diffusion characteristics (Mori et al., 1999; Assaf and Pasternak, 2008; Neil, 2008). In normal white matter, water molecules move relatively freely in a direction parallel to nerve fiber tracts, however, their movements are restricted across tracts, which cause diffusion anisotropy in white matter. This selective restriction of water molecule movement allows for exploration of physical changes in white matter caused by normal aging using diffusion anisotropy. Some studies using DTI have reported on changes in periventricular white matter in patients with stroke or other brain injuries (Yeo et al., 2011; Hattori et al., 2012; Jang et al., 2013). In the current study, using DTI, we investigated ventricular enlargement with normal aging, and its effect on periventricular white matter.

The human brain is known to have six cholinergic nuclei (Selden et al., 1998; Nieuwenhuys et al., 2008). The cerebral cortex obtains cholinergic innervation mainly from the basalis nucleus of Meynert (Ch 4) in the basal forebrain through the medial and lateral cholinergic pathways (Selden et al., 1998; Mesulam et al., 1983). The cingulum, the neural fiber bundle connecting the basal forebrain and the medial temporal lobe, contains the medial cholinergic pathway (Selden et al., 1998; Hong and Jang, 2010). In addition, the other cholinergic nuclei in the basal forebrain (Ch 1: medial septal nucleus, Ch 2: vertical nucleus of the diagonal band) are connected to the cingulum (Nieuwenhuys et al., 2008). Therefore, the cingulum is an important pathway for cholinergic innervation for the cerebral cortex. On the other hand, two cholinergic nuclei are located in the brainstem (Ch 5: pedunculopontine nucleus and Ch 6: laterodorsal tegmental nucleus), and are connected to the thalamus (Nieuwenhuys et al., 2008; Mesulam, 1990; Wainer et al., 1993; Lucas-Meunier et al., 2003). Many studies have reported connections between the cholinergic nuclei, especially between the cholinergic nuclei in the basal forebrain and those in the brainstem via the fornix and thalamus (Mesulam, 1990; Wainer et al., 1993; Woolf and Butcher, 1986; Marina et al., 2002; Paxinos, 2004). However, little is known about the connection between cholinergic nuclei in the basal forebrain and cholinergic nuclei in the brainstem via the cingulum (Yeo et al., 2012). Diffusion tensor tractography (DTT), derived from diffusion tensor imaging (DTI), has the unique advantage of allowing for three-dimensional visualization and estimation of neural tracts in the live human brain (Concha et al., 2005; Malykhin et al., 2008; Yeo et al., 2013). A recent DTT study reported an unusual neural connection between an injured cingulum and a cholinergic nucleus in the brainstem in a patient with traumatic brain injury, suggesting a recovery mechanism following cingulum injury (Yeo et al., 2012). However, no study on this phenomenon in other brain pathology has been reported. In this study, we report on a patient who showed unusual neural connections between injured cingulums and brainstem cholinergic nuclei following aneurysmal subarachnoid hemorrhage, using DTT. Ten age- and sex-matched normal control subjects (seven males; mean age: 27.57 years) were recruited for control. A 50-year-old male patient underwent craniotomy and clipping for a ruptured aneurysm of the anterior communicating artery after subarachnoid hemorrhage at the neurosurgery department of a university hospital (Figure 1A). At 4 weeks after onset, he was transferred to the rehabilitation department of the same hospital. Brain MRI taken at 4 weeks after onset showed leukomalactic lesions in the left frontal lobe (Figure 1A). The patient showed memory impairment at 5 weeks after onset: Wechsler Adult Intelligence Scale: 104, and the Memory Assessment Scale (global memory: 79 (8%ile), short term memory: 111 (77%ile), verbal memory: 94 (35%ile), and visual memory: 71 (3%ile) (Wechsler, 1981; Williams, 1991). His memory function showed improvement, within normal range, at 7 months after onset: Wechsler Adult Intelligence Scale: 125, and the Memory Assessment Scale (global memory: 104 (61%ile), short term memory: 114 (83%ile), verbal memory: 111 (77%ile), and visual memory: 97 (42%ile) (Mesulam, 1990; Williams, 1991). Figure 1 DTT and CT images in a 50-year-old male patient ongoing craniotomy and clipping for a ruptured aneurysm of the anterior communicating artery after SAH. A 6-channel head coil on a 1.5-T Philips Gyroscan Intera scanner (Hoffman-LaRoche, Ltd., Best, the Netherlands) was used for acquisition of DTI data two times at 1 and 7 months after onset. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissure-posterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed to matrix = 192 × 192; field of view = 240 mm × 240 mm; repetition time = 10,398 ms; echo time = 72 ms; b = 1,000 s/mm2; number of excitations = 1; and slice thickness = 2.5 mm. The fiber assignment continuous tracking (FACT) algorithm was used in performance of fiber tracking (Stieltjes et al., 2001). The cingulum areas were reconstructed using fibers passing through two regions of interest (middle and posterior portion of the cingulum). Termination criteria were fractional anisotropy 27° (Yeo et al., 2012; Malykhin et al., 2008). On both 1- and 7-month DTTs of the patient, we observed discontinuations of both cingulums above the genu of the corpus callosum. On 1-month DTT, both cingulums were connected to each Ch 5 bilaterally via the neural tracts that passed through the thalamus; in contrast, the left neural tract had disappeared on 7-month DTT and the right neural tract was connected to the right Ch 6 (Figure 1B). In this study, we found unusual neural connections between the injured cingulums and the brainstem cholinergic nuclei in a patient with aneurysmal subarachnoid hemorrhage. The patient showed severe injury of both anterior cingulums on 1- and 7-month DTT. On 1-month DTT, the neural connections between the anterior portion of injured cingulums and Ch 5 were observed in both hemispheres. By contrast, on 7-month DTT, the left neural connection had disappeared and the right neural connection was connected to Ch 6 instead of Ch 5. These neural connections between the cingulum and the cholinergic nuclei were not observed in any of the control subjects. We assume that these neural connections resulted from an attempt for neural reorganization by the injured cingulum in order to obtain cholinergic innervation from the brainstem cholinergic nuclei after losing cholinergic innervation from cholinergic nuclei in the basal forebrain. The fact that the patient showed good cognition, including memory function, appears to be additional evidence for this assumption. The brain has the characteristics of plasticity for reorganization following an injury. The basic mechanisms of brain plasticity are as follows: collateral sprouting from intact cells to a denervated region after normal input has been destroyed and unmasking of reserve axons and synapses for particular functions after failure of the normally dominant system (Bach-y-Rita, 1981; Bach y Rita, 1981). The fact that the unusual neural connections between the injured cingulum and brainstem were observed during early stage after onset on 1-month DTT might indicate that these connections were attributed to the unmasking of an already existing latent neural pathway rather than collateral sprouting. Further follow up studies from the acute stage to chronic stage after the onset of subarachnoid hemorrhage will be necessary in order to clarify this topic. In conclusion, we report on a patient who showed unusual neural connections between the anterior portion of injured cingulums and the brainstem cholinergic nuclei. We believe that our findings may suggest one of the recovery mechanisms for cholinergic innervations of injured cingulums in patients with subarachnoid hemorrhage. A similar phenomenon was reported in a patient with traumatic brain injury, who showed a neural connection between the injured cingulum and Ch 5 (Yeo et al., 2012). Therefore, this is the first study to report on unusual neural connection in stroke patients. Further studies on the clinical significance of this unusual neural connection should be encouraged.

The corticospinal tract (CST) is an essential motor pathway in the human brain: particularly, it is essential for fine hand movements (Jang, 2014). Stroke patients can show more severe weakness when a partial injury of the CST is combined with apraxia. Therefore, a thorough estimation of the CST injury degree at the beginning of stroke rehabilitation would be mandatory for a successful rehabilitation. In this study, we report on a case in whom partially injured CST had been neglected due to accompanying apraxia for 10 months. A 71-year-old female patient was transferred for rehabilitation of hemiplegia after cranioplasty. The patient had undergone decompressive craniectomy for brain swelling due to a left middle cerebral artery (MCA) territory infarct which occurred after clipping of a ruptured left MCA bifurcation aneurysm 10 months ago at the same hospital. The patient had presented with complete paralysis (manual muscle test (Wadsworth et al., 1987): 0) of the right side (upper and lower extremities) for 10 months since the onset of cerebral infarct, although she had undergone rehabilitation at a local rehabilitation hospital for 10 months. Brain CT and brain MRI (2 days and 10 months after onset, respectively) showed a large infarct in the left MCA territory except for some portion of the left precentral gyrus (Figure 1A). The ideomotor apraxia test scores were 40 points (cut-off score < 32 points) (De Renzi et al., 1980). The patient was involved in a comprehensive rehabilitative therapy, including dopaminergic drugs for improvement of apraxia (pramipexole 1.5 mg; ropinorole 0.75 mg; amantadine 300 mg; levodopa, 750 mg) (Jang, 2013). During 3 weeks of rehabilitation treatment, the patient exhibited significant motor improvement in the right side (upper and lower extremities) to the extent that she was able to move against gravity (manual muscle test: 3). The patient provided signed, informed consent and our hospital review board approved the study protocol. Figure 1 CT, T2-weighted MRI and diffusion tensor tractography (DTT) images in a stroke patient. Diffusion tensor imaging (DTI) data were acquired once (10 months after onset) using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips Healthcare, Best, the Netherlands) with single-shot echo-planar imaging. Seventy contiguous slices (acquisition matrix = 96 × 96, reconstructed to matrix = 192 × 192, field of view (FOV) = 240 × 240 mm2, repetition time (TR)/echo time (TE) = 10,398/72 ms, SENSE factor = 2, echo planar imaging (EPI) factor = 59, b = 1,000 s/mm2, number of excitations = 1, thickness = 2.5 mm) were acquired. Fiber assignment continuous tracking (FACT) algorithm was used for fiber tracking. The CST was reconstructed using fibers passing through two regions of interest (ROIs) on the color map. The first ROI and second ROI were given on the blue portion (anterior) of the upper and lower pons, respectively on the axial image of the color map (threshold fractional anisotropy = 0.15, angle = 27). The left CST was narrowed compared with the right CST; however, the integrity was preserved from the cerebral cortex to the medulla (Figure 1B). Transcranial magnetic stimulation (TMS) was carried out using a Magstim Novametrix 200 magnetic stimulator (Novametrix Inc., Wallingford, CT, USA) at 10 months after onset. Cortical stimulation was performed (left hemisphere: a counterclockwise direction; right hemisphere: a clockwise direction). Motor-evoked potentials (MEPs) were recorded from the right thumb muscle (abductor pollicis brevis) upon stimulation of the left hemisphere with 90% of maximal output (the MEP of shortest latency; latency: 23.7 ms, amplitude: 100 µV, excitatory threshold: 70%). In this patient, some portion of the left precentral gyrus, which is the essential origin of the CST, was preserved on 2-day brain CT and 10-month brain MRI, thus it appeared that the left CST integrity had been preserved since the left MCA infarct (Jang, 2014). In addition, MEP, which has the characteristics of the CST, was evoked at the right hand muscle on 10-month TMS (Rossini et al., 1994). Therefore, we believe that the left CST, which was partially damaged by the MCA infarction, had been in limb apraxia state for 10 months since the onset. Limb apraxia is a common disorder of skilled purposive movement; three types of limb apraxia have been reported: ideational apraxia, ideomotor apraxia, and limb-kinetic apraxia (Leiguarda and Marsden, 2000; Ochipa and Gonzalez Rothi, 2000; Hong et al., 2012; Jang, 2013). Limb-kinetic apraxia is attributable to injury of the premotor cortex with preservation of CST integrity (Leiguarda and Marsden, 2000; Ochipa and Gonzalez Rothi, 2000; Hong et al., 2012; Jang, 2013). Precise diagnosis of limb-kinetic apraxia is difficult because it is made by clinical observation of movements without use of specific evaluation tools (Hong et al., 2012; Jang, 2013). In this patient, brain MRI findings involving the fronto-parietal cortex suggested the possibility of limb-kinetic apraxia and ideomotor apraxia; however, because the patient showed an intact ideational plan for motor performance in the ideomotor apraxia test, we think that the motor improvement for 3 weeks since 10 months after onset was mainly attributed to the resolution of limb-kinetic apraxia (De Renzi et al., 1980). Our results suggest the importance of thorough evaluation of the damage degree of the tracts at the beginning of stroke rehabilitation. However, limitation of using DTI in this study should be taken into account. Fiber tracking is an analyzer dependent method. In addition, DTI might underestimate the neural fibers due to the fiber-crossing effect (Lee et al., 2005; Yamada et al., 2009). This work was supported by the DGIST R&D Program of the Ministry of Science, ICT and Future Planning (15-BD-0401). SHJ designed this study, collected and analyzed data, and revised the paper. CHC participated in study design and data collection. WHJ participated in data collection and analysis and wrote the paper. All authors approved the final version of this paper.

Ventriculoperitoneal shunting is a commonly used neurosurgical procedure for management of hydrocephalus (Jang et al., 2015). Various complications of ventriculoperitoneal shunting have been reported, including infection, hemorrhage, shunt malfunction, shunt displacement and brain swelling (Kwon and Jang, 2012, 2015). Although ventriculoperitoneal shunting can cause injury of adjacent neural tracts, little is known about injury of the neural tract by ventriculoperitoneal shunting (Kwon and Jang, 2013). Diffusion tensor tractography (DTT), derived from diffusion tensor imaging (DTI), enables visualization and estimation of neural tracts in three dimensions (Gold et al., 2008). A previous study using DTT has reported on injury of neural tracts by invasive neurosurgical procedures such as extraventricular drainage or shunt operation (Kwon and Jang, 2013). However, it has not been clearly elucidated so far. In the current study, using DTT, we attempted to demonstrate injury of the corticoreticular pathway (CRP) and corticospinal tact (CST) caused by ventriculoperitoneal shunting in a patient with normal pressure hydrocephalus. A 70-year-old female patient who showed gait disturbance for 1 year and enlarged ventricles on the brain CT was diagnosed with normal pressure hydrocephalus at the department of neurosurgery of a university hospital. She underwent ventriculoperitoneal shunting approached through the right posterior parietal area in the brain. Brain CT and T2 weighted MRI after shunt operation revealed hemorrhage at the corona radiata around the passage of the ventriculoperitoneal shunt (Figure ​Figure1A,1A, ​,BB). After the shunt operation, the patient developed the left hemiparesis and gait difficulty as follows (based on Medical Research Council [MRC] and Functional Ambulation Category [FAC]) (Cunha et al., 2002; Paternostro-Sluga et al., 2008): The MRC score was used for evaluation of motor function: 0, no contraction; 1, palpable contraction but no visible movement; 2, movement without gravity; 3, movement against gravity; 4, movement against a resistance lower than the resistance overcome by the healthy side; and 5, movement against a resistance equal to the maximum resistance overcome by the healthy side (Paternostro-Sluga et al., 2008). The FAC was designed for examination of the levels of assistance required during a 15-m walk. Six categories are included in the FAC: 0 (non-ambulatory), 1 (needs continuous support from one person), 2 (needs intermittent support from one person), 3 (needs only supervision and verbal cues), 4 (help is required on stairs and uneven surfaces), and 5 (can walk independently anywhere) (Cunha et al., 2002). The patient provided signed, informed consent and our institutional review board approved the study protocol. Figure 1 CT, T2 weighted MRI and diffusion tensor tractography (DTT) images of a 70-year-old female patient undergoing ventriculoperitoneal (VP) shunting approached through the right posterior parietal area in the brain. DTI was acquired at 1 month after the shunt operation using a six-channel head coil on a 1.5-T Philips Gyroscan Intera (Philips, Ltd, Best, The Netherlands) with single-shot echo-planar imaging. Imaging parameters were as follows: acquisition matrix = 96 × 96, repetition time = 10,398 ms, echo time = 72 ms, echo planar factor = 59 and b = 1,000 s/mm2, number of excitations = 1, slice gap = 0 mm and a slice thickness of 2.5 mm. Fiber tracking for the CRP and CST was performed using the fiber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software. The left CRP and CST showed intact integrities from the cerebral cortex to the medulla. By contrast, the right CRP showed discontinuation at the passage of the shunt of the right corona radiata and degeneration to the right midbrain. In addition, the anterior portion of the right CST also showed discontinuation at the passage of the shunt of the right corona radiata compared with the left CST (Figure 1C). In the current study, using DTT, we demonstrated injury of the CRP and CST following ventriculoperitoneal shunting in a patient with normal pressure hydrocephalus. Injury of the right CRP and CST in this patient appeared to have resulted from ventriculoperitoneal shunting or ventriculoperitoneal shunting combined with hematoma caused by ventriculoperitoneal shunt operation. We think that the motor weakness of the left upper and lower extremities in this patient was ascribed to injury of the CRP and CST. Furthermore, the characteristics of the motor weakness were compatible with the injury of these motor tracts: more severe weakness of the left proximal joint muscle than the left distal joint muscles, indicating the injury of the right CRP, and milder weakness of the left distal joint muscles than the left proximal joint muscles, indicating the partial injury of the right CST (Jang et al., 2015). Although many studies have reported on the complications of invasive procedures such as extraventricular drainage or shunt operation, injuries of neural tracts in the brain caused by these procedures have rarely been reported (Gold et al., 2008; Kwon and Jang, 2012, 2013, 2015). The injured neural tracts were as follows: CST, cingulum, fornix, and CRP. Regarding the CRP and CST, Gold et al. (2008) reported on a patient who presented with direct injury of the CST during revision of a ventriculoperitoneal shunt. Kwon and Jang (2015) reported on patients with intracerebral hemorrhage who showed injury of the CRP following external ventricular drainage (Gold et al., 2008; Kwon and Jang, 2015). As a result, to the best of our knowledge, this is the first study to demonstrate combined injury of the CRP and CST following ventriculoperitoneal shunting. This work was supported by the National Research Foundation (NRF) of Korea funded by the Korean Government (MSIP), No. 2015R1A2A2A01004073. SHJ conceived and designed this study, was responsible for fundraising, data acquisition, and paper development and writing. JPS was responsible for data acquisition, paper development, writing, and authorization. Both of these two authors approved the final version of this paper.

The corticoreticular pathway (CRP) mainly mediates proximal and axial muscles and therefore it is an important neural tract for walking (Miyai et al., 2002; Matsuyama et al., 2004; Mendoza and Foundas, 2007). Diffusion tensor tractography (DTT), derived from diffusion tensor imaging (DTI), enables reconstruction of the CRP three-dimensionally and several studies have reported on the association between the CRP and gait recovery (Yeo et al., 2012a, 2013; Jang et al., 2013, 2015; Jang and Seo, 2014; Kwon and Jang, 2014). However, to the best of our knowledge, there has been no report on degeneration of the CRP. In the current study, we reported on a patient with intracerebral hemorrhages (ICHs) in both hemispheres, presenting with gait deterioration due to neural degeneration of the CRP as shown on DTT images. A 64-year-old male presented with gait deterioration which started 2 months ago. He had a history of spontaneous ICHs in both putamens (the right ICH: 19 years ago, and the left ICH: 11 years ago). The patient's motor weakness was measured using Medical Research Council (MRC) scale (Council, 1976). His walking ability was assessed using Functional Ambulatory Category (FAC) (Cunha et al., 2002). Before the onset of gait deterioration, his motor function had recovered to a subnormal state in the right extremities and a nearly normal state in the left extremities; therefore, he was able to walk independently, even on stairs (FAC: 4). Since about 2 months ago, his gait function had begun to deteriorate and aggravated progressively with time. Two months after the onset of gait disturbance, he could not walk independently, even on floors (FAC: 1.5). He presented with weakness of proximal joints along with more severe weakness in the right extremities compared with the left side (MRC scale, shoulder abductor: 4-/4, elbow flexor: 4/4+, finger extensor: 4/4+, hip flexor: 4-/4, knee extensor: 4/4+, ankle dorsiflexor: 4/4+) (Council, 1976). Brain MR images taken at 2 months after onset of gait deterioration showed leukomalactic lesions in both subcortical white matter and basal ganglia (Figure 1B). Figure 1 Brain CT and MR images and results of diffusion tensor tractography (DTT) in a 64-year-old male patient with gait deterioration. DTI data were obtained twice (first DTI: 6 years ago and second DTI: 2 months after onset of gait deterioration). Sixty contiguous slices (field of view = 240 × 240 mm2; repetition time = 10,726 ms; echo time = 76 ms; b = 1,000 s/mm2; number of excitations = 1; and thickness = 2.5 mm) were acquired. FACT algorithm was used for fiber tracking. The CRP was reconstructed using fibers passing through two regions of interest (ROIs) on the color map. The first ROI was given at the medullary reticular formation and the second ROI at the midbrain tegmentum. Termination criteria used for fiber tracking were fractional anisotropy (FA) of less than 0.2 and angle of less than 60°. On the first DTT scan performed 6 years ago, the integrities of the CRPs in both hemispheres were preserved from the cerebral cortex to the medulla. By contrast, on the second DTT taken at 2 months after onset of gait deterioration, both CRPs showed discontinuation at the corona radiata level compared with the first DTT (Figure 1C). In this study, the gait deterioration in this patient was ascribed to delayed neural degeneration of both CRPs. The patient began to show gait deterioration 2 months ago, before undergoing the second DTT. The second DTT for the CRP, taken at 2 months after onset of gait deterioration, showed discontinuations at the corona radiata compared with the first DTT (6 years ago), which showed that integrities of both CRPs were intact. This finding was consistent with the characteristics of motor weakness of the patient (more severe weakness of proximal muscles) (Matsuyama et al., 2004; Mendoza and Foundas, 2007; Yeo et al., 2013). Regarding the pathophysiological mechanism of delayed neural degeneration of the CRP in the corona radiata, injury of peri-lesional white matter might occur through a chemical mechanism: a blood clot might release potentially toxic substances which can induce injury to neural tissue, such as free iron, which might release free radicals or inflammatory cytokines (Chua et al., 2009; Yeo et al., 2012b). However, other factors that can deteriorate the gait function such as normal aging or physical deconditioning should be also considered. Accompanying neural degeneration is often observed after stroke (Yu et al., 2009; Puig et al., 2010). Many studies have reported on Wallerian degeneration that started immediately after neuronal injury in the acute stage of stroke (Yu et al., 2009; Puig et al., 2010). Wallerian degeneration is a process characterized by degeneration of axons and their distal part myelin sheath in the central and peripheral nervous system. However, little is known about delayed neural degeneration in stroke patients. To the best of our knowledge, this is the first study to report on neural degeneration of the CRP although a few previous studies have reported on neural degeneration of the CST in stroke patients (Radlinska et al., 2009; Jang ans Seo, 2016). However, DTI might underestimate the neural fibers due to the fiber-crossing effect (Yamada et al., 2009), which should be considered. In conclusion, we report on a patient who showed delayed gait deterioration due to neural degeneration of the CRP. We believe that DTT evaluation of the CRP would be helpful to elucidate the mechanism behind delayed gait deterioration in stroke patients. This work was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (MSIP), No. 2015R1A2A2A01004073.

A 34-year-old male patient underwent conservative management for traumatic hemorrhage in the right frontal lobe (Figure 1A). The patient lost consciousness for approximately 4 weeks and experienced post-traumatic amnesia continuously from the time of the accident. The patient's Glasgow Coma Scale score (Teasdale et al., 1974) was 6 when he arrived at the hospital. At 5 weeks after onset, he was transferred to the rehabilitation department to undergo rehabilitation. Brain MRI showed malactic lesions in both the frontal lobes and right thalamus (Figure 1B). The patient exhibited impaired consciousness, with a Glasgow Coma Scale score of 9 and Coma Recovery Scale-Revised score of 8 (Giacino et al., 2004). Figure 1 Brain CT images, magnetic resonance images and diffusion tensor tractography (DTT) images of a 34-year-old male patient with traumatic brain injury. Diffusion tensor tractography (DTT) data were obtained at 6 weeks after onset using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Best, the Netherlands) with single-shot echo-planar imaging. Imaging parameters were as follows: acquisition matrix = 96 × 96; reconstructed matrix = 192 × 192; field of view = 240 × 240 mm2; repetition time = 10,726 ms; echo time = 76 ms; parallel imaging reduction factor (SENSE factor) = 2; EPI factor = 49; b = 1,000 s/mm2; number of excitations = 1; and a slice thickness of 2.5 mm. FACT algorithm was used for fiber tracking. For ascending reticular activating system (ARAS) analysis, the seed region of interest (ROI) was given on the pontine reticular formation. According to previous reports (Yeo et al., 2013; Jang et al., 2014), the target ROI was placed on the thalamic intralaminar nuclei to analyze the connectivity of the intralaminar nuclei. The patient showed intact neural connectivity between the thalamic intralaminar nuclei the frontal lobe. However, the left lower ARAS between pontine reticular formation and thalamic intralaminar nuclei was thinner than the right lower one of the same patient and those in five age-matched healthy control subjects (Figure 1C). In this study, we evaluated the ARAS in a patient with severe traumatic brain injury through two portions: First, three-dimensional reconstruction at the lower ARAS between the pontine reticular formation and the thalamic intralaminar nuclei, second, neural connectivity of the upper ARAS between the thalamic intralaminar nuclei and the cerebral cortex. Our results showed that the left lower ARAS was thinner than that of the right side of the patient and those of normal subjects. These findings appear to suggest an injury of the left lower ARAS. This injury was attributed to traumatic axonal injury because the conventional brain MRI of the patient was normal in the left thalamus and brainstem. Before analysis of the ARAS, we assumed that the main lesion would be located in the right ARAS and left upper ARAS because the brain MRI showed malactic lesions in both frontal lobes and the right thalamus. The main lesion site was detected in the left lower ARAS between the thalamic reticular formation and the thalamic intralaminar nuclei (Edlow et al., 2013; Jang et al., 2015a, b). Our results suggest that analysis of the ARAS using DTT would be useful for elucidating the cause of impaired consciousness. However, limitation of DTT with 1.5 T MRI should be considered, because a higher tesla MRI such as 3.0 T, can show better resolution and identify small tract more precisely. This work was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (MSIP), No. 2015R1A2A2A01004073.

Disorder of consciousness (DOC) is one of the most serious sequelae of brain injury, and is challenging for neurologists and rehabilitation specialists to manage because of its refractory nature (Whyte et al., 2013). Acupuncture is a traditional Chinese medicine technique that is often used to help improve the level of consciousness in patients with DOC. However, the responses to stimulation of acupoints in patients with DOC are not fully understood. It is unclear whether stimulation of acupoints simply provides peripheral sensory input, or whether such stimulation induces specific responses that differ from those of other sensory input. To investigate these responses, we studied five patients with DOC who received acupuncture at real and sham acupoints from January 2012 to June 2013. Positron emission tomography (PET) findings were used to study the effects of the two acupuncture procedures on neuronal activation in the brain. Patient 1 was a 45-year-old female who had not regained consciousness since an anesthetic accident in January 2009, and was admitted to the China Rehabilitation Research Center in June 2012. She started to open her eyes spontaneously 6 months after the anesthetic accident, but showed no other signs of recovery. Cranial computed tomography (CT) in June 2012 showed diffuse hypoxic brain injury, global atrophy and compensating hydrocephalus. Assessment using the Coma Recovery Scale-Revised (CRS-R) (Kalmar and Giacino, 2005) indicated a vegetative state (Tables ​(Tables1,1, ​,2),2), and she was admitted for conventional rehabilitation. Table 1 Baseline data of five patients Table 2 CRS-R assessment of the five patients at admission Patient 2 was a 47-year-old female who had not regained consciousness since a car accident in August 2011 during which she sustained multiple fractures and internal hemorrhage, and was admitted to the China Rehabilitation Research Center in June 2012. Cranial CT showed diffuse neuronal injury. She was clinically stable after 3 months of treatment, and opened her eyes spontaneously without external stimulation. Assessment using the CRS-R indicated a vegetative state (Tables ​(Tables1,1, ​,2),2), and she was admitted for conventional rehabilitation. Patient 3 was a 65-year-old male who had not regained consciousness since the rupture of an intracranial aneurysm. Cranial CT showed intracerebral hemorrhage between the ventricles and blood in the ventricles. He underwent intravascular embolization and ventricular drainage on the day of the rupture. He opened his eyes spontaneously but was unable to communicate. He was admitted to the China Rehabilitation Research Center in June 2012. Assessment using the CRS-R indicated a vegetative state (Tables ​(Tables1,1, ​,2),2), and he was admitted for conventional rehabilitation. Patient 4 was a 55-year-old female with a 10-year history of hypertension who had not regained consciousness since an intracranial hemorrhage in July 2011. Cranial CT showed intracerebral hemorrhage in the right thalamus and blood in the ventricles. She underwent decompressive craniectomy and evacuation of the hematoma on the day of the hemorrhage. She started opening her eyes spontaneously 1 month after surgery, but had limited responses to external stimuli. She underwent ventriculoperitoneal shunt placement for hydrocephalus. She was admitted to the China Rehabilitation Research Center in June 2012 for conventional rehabilitation. Assessment using the CRS-R indicated a minimally conscious state (Tables ​(Tables1,1, ​,22). Patient 5 was a 14-year-old male who had not regained consciousness since accidental ingestion of pesticide in October 2012. He started to open his eyes spontaneously 2 months after the accident, but did not communicate. His level of consciousness gradually improved, and he became more responsive to external stimuli. He was admitted to the China Rehabilitation Research Center in March 2013 for conventional rehabilitation. Assessment using the CRS-R indicated a minimally conscious state (Tables ​(Tables1,1, ​,22). Intervention after admission: (1) Each patient received acupuncture at bilateral sham acupoints (1 cm lateral to KI 1) during the first scan and at bilateral Yongquan acupoints (KI 1, located on the sole of the foot, between the second and third metatarsal bones at the indentation near the front, one-third of the distance from the webs of the toes to the heel) during the second scan, which was performed 3 days after the first scan. (2) All scans were performed at 11:00 a.m., and all patients rested in a dark room for 30 minutes before scanning. CT was performed first, and patients were then injected with 18-fluorodexyglucose (18-FDG) 10 mCi (Chinese PLA General Hospital, synthetized using an Explora FDG4 GE TRACERlab MX FDG Synthesizer accelerator, General Electric Co., Fairfield, Connecticut, USA). PET (Discovery STE scanner, General Electric Co.) was started immediately after injection of 18-FDG. The scan lasted for 50 minutes and dynamic PET data were collected. (3) Acupuncture was performed by an experienced acupuncturist for 30 minutes during the PET scan. The acupuncturist twisted acupuncture needles in alternating clockwise and anticlockwise directions (once per second, ≥ 360°, for 1 minute) every 10 minutes from the start of PET. (4) The following parameters were used for PET: axial field of view: 15 cm; bed: 1; collection mode: 3D reconstruction, 2 iterations, 21 subsets, diameter 2 mm. PET data were reconstructed with slice thickness 3.73 mm, slice interval 1 mm, and matrix size 128 × 128. (5) PET-CT images were processed using Statistical Parametric Mapping software (SPM2; The Welcome Department of Cognitive Neurology, University College London, UK). After realignment, the images were normalized using the Montreal Neurological Institute template and then smoothed using a Gaussian kernel with 6 mm full width at half-maximum. The half-width of the X, Y and Z axes was 10 mm. Spatial data were determined using SPM2 software, and differences between the two acupuncture procedures were analyzed using the paired t-test. (6) Differences between the two acupuncture procedures were analyzed using the t-test to acquire the t and Z values of corresponding pixel points, and a statistical parameter map was constructed based on t/Z values. The threshold for statistical significance was set at P 5 voxels. For P = 0.001 (t = 4.303) and extent threshold ≤ 300, there was significantly higher metabolism in the left putamen, left anterior cingulate cortex, left gyri orbitales, bilateral cerebellar hemispheres and right paracentral lobule during stimulation of the Yongquan acupoints than the sham acupoints (Table 3, Figure 1). Table 3 Brain areas activated by acupuncture in patients with disorder of consciousness: sham acupoints versus Yongquan (KI1) acupoints Figure 1 Brain activation during acupuncture at the Yongquan acupoint (KI1) in five patients. Neuronal activity can be observed on PET after injection of 18F-FDG, which shows areas of synaptic firing in the brain (Hsieh et al., 2011; Eidelberg et al., 1997). The results of this study show that acupuncture at the Yongquan acupoints induced stronger neuronal activity than acupuncture at the sham acupoints. We believe that acupuncture at the Yongquan acupoints may increase synaptic activity in some areas of the brain. The putamen (Palmiter, 2011), cingulate cortex, frontal lobe (Boly et al., 2013) and cerebellum (Sullivan, 2010) are involved in conscious thought. Long-term acupuncture may affect the quantity and function of synapses in these areas, leading to neural reorganization. This may explain the mechanism by which acupuncture at the Yongquan acupoints results in improvement of patients with DOC.

The less affected hemisphere is important in motor recovery in mature brains. However, in terms of motor outcome in immature brains, no study has been reported on the less affected corticospinal tract in hemiplegic pediatric patients. Therefore, we examined the relationship between the condition of the less affected corticospinal tract and motor function in hemiplegic pediatric patients. Forty patients with hemiplegia due to perinatal or prenatal injury (13.7 ± 3.0 months) and 40 age-matched typically developing controls were recruited. These patients were divided into two age-matched groups, the high functioning group (20 patients) and the low functioning group (20 patients) using functional level of hemiplegia scale. Diffusion tensor tractography images showed that compared with the control group, the patient group of the less affected corticospinal tract showed significantly increased fiber number and significantly decreased fractional anisotropy value. Significantly increased fiber number and significantly decreased fractional anisotropy value in the low functioning group were observed than in the high functioning group. These findings suggest that activation of the less affected hemisphere presenting as increased fiber number and decreased fractional anisotropy value is related to poor motor function in pediatric hemiplegic patients.

Diffuse axonal injury (DAI) is axonal and small vessel injury produced by a sudden acceleration of the head by an external force, and is a major cause of death and severe disability (Paterakis et al., 2000). Prognosis is poorer in patients with apparent hemorrhage than in those without (Paterakis et al., 2000). Therefore, it is important to identify the presence and precise position of hemorrhagic foci for a more accurate diagnosis. CT and magnetic resonance imaging (MRI) have long been applied in the diagnosis of DAI, but they are not sensitive enough for the detection of small hemorrhagic foci, and cannot meet the requirements for early diagnosis. A major advance in MRI has been the development of susceptibility weighted imaging (SWI), which has greatly increased the ability to detect small hemorrhagic foci after DAI (Ashwal et al., 2006). In this study, we retrospectively analyzed MRI data for 25 patients with hemorrhagic DAI verified by clinical imaging, and we explored whether SWI was sufficiently sensitive to evaluate hemorrhagic DAI and help accurately assess the severity of the disease.

The ipsilateral motor pathway from the unaffected motor cortex to the affected extremity is one of the motor recovery mechanisms following stroke (Jang, 2011). Because stroke patients who had shown recovery by this mechanism usually showed poorer motor function, compared with patients who showed recovery by other mechanisms, several researchers have considered this mechanism as a maladaptive plasticity (Jang, 2013).

Extensive lesions involving the posterior quadrant of the cerebral hemisphere (temporal, parietal, and occipital lobes) induce intractable epilepsy. These patients are potential candidates for surgical treatment[1]. Maintenance of isolated nerve tissue activity after surgery plays a crucial role in the neuroprotective effects of neurosurgery treatment. Disconnection surgery of the posterior quadrant is used to completely isolate nerve fibers, while blood supply at the isolated lobes is maintained. Subsequently, cavities caused by cystic or necrotic nerve tissues should be reduced as much as possible, to maintain the activity of isolated nerve tissue[1,2,3,4]. In this study, we selected two patients with temporal-parietal-occipital intractable epilepsy, from the Department of Neurosurgery, Tianjin Huanhu Hospital and Tianjin Neurological Institute (Tianjin, China), between February and May in 2012. The two cases underwent post quadrant disconnection. After surgery, activity of temporal-parietal-occipital nerve tissue and the control of epileptic seizures were observed. Case 1: An 11-year-old male, was admitted to Tianjin Huanhu Hospital in February, 2012, and received surgery 1 week later. Postoperative follow-up was performed every 6 months. The medical history showed mild head injury when he was 5 years old, resulting from a scalp laceration without loss of consciousness. The first seizure occurred 1 year later, with the head turning towards the left side, without limb and trunk spasms. He was conscious, and the seizure stopped after 2 minutes. After the second attack, he was diagnosed and treated for epilepsy. Control of seizures failed after 3 anticonvulsant treatments, became refractory, and he still had one seizure per week, while being treated with a combination of 3 anticonvulsants. Preoperative physical examination showed left homonymous hemianopsia. Video-electroencephalography monitoring showed interictal spikes and slow wave complexes in the right central occipital region (Figure 1A1). Magnetic resonance imaging (MRI) of the brain revealed right occipital congenital porencephaly (Figure 1A2). Based upon these findings, this case was diagnosed as simple partial epilepsy. The left hemisphere was not involved during the seizure, because language function was not affected. Video-electroencephalography monitoring and brain imaging results, as well as the clinical features, identified the epileptogenic region as the right post quadrant. A right post quadrant disconnection was therefore performed. Figure 1 Electroencephalogram (EEG) and MRI changes of case 1, an 11-year-old male patient with temporal-parietal-occipital epilepsy, before and after posterior quadrant disconnection. After surgery, the patient orally received 300 mg of oxcarbazepine, twice a day, for an extended period. Follow-up was performed every 6 months. Six month postoperative electroencephalogram showed no epileptic waves (Figure 1B1). MRI revealed complete resection of the right posterior temporal-parietal-occipital lobes, and the majority of isolated brain tissue produced normal signals (Figure 1B2). Case 1 was followed-up for 22 months, during which time no aura or seizure was observed. Case 2: A 28-year-old female was admitted to Tianjin Huanhu Hospital in April, 2012, and received surgery 1 week later. Medical history showed no remarkable features such as brain injury or infection. The first attack occurred 6 months before admission, involving generalized tonic-clonic seizures and disturbance of consciousness, which continued for 1–2 minutes, and then stopped. She was diagnosed with epilepsy and received anticonvulsant medication after a secondary seizure 2 months before admission. However, the seizures were not controlled, and a brain CT scan at a local hospital revealed suspicious “gray matter heterotopia”. Preoperative physical examination showed no seizure attacks during 3 days of video-electroencephalography monitoring. Interictal electroencephalogram showed interrupted short-range low and middle amplitude waves in the right hemisphere. There were also some interictal spikes and slow wave complexes, especially in the temporal and parietal regions (Figure 2A1). MRI of the brain showed an irregular and abnormal signal isodensity with gry matter subendymal at the atrium of the right ventricle. Similar signals were also observed in the temporal horn of the ipsilateral ventricle under the ventricular ependyma (Figure 2A2). The neuroimaging and electroencephalogram therefore showed an epileptogenic focus at the posterior right hemisphere, and posterior quadrant disconnection was performed with the same surgical procedures as case 1. Figure 2 Electroencephalogram (EEG) and MRI changes of case 2, a 28-year-old female patient with temporal-parietal-occipital epilepsy, before and after posterior quadrant disconnection. After surgery, the patient orally received 500 g of sodium valproate, twice a day, for an extended period. A 6 month postoperative electroencephalogram showed no epileptic waves (Figure 2B1). MRI revealed complete resection of the right posterior quadrant, but nerve tissue still survived (Figure 2B2). Case 2 was followed up for 20 months, during which time no seizures were observed. The involved two patients were informed of the experimental scheme and risk prior to treatment, and both patients signed informed consents. Disconnection surgery of the posterior quadrant is used to cut nerve fibers between the posterior quadrant and the resting region in the hemisphere, isolating the epileptogenic zone at the posterior quadrant. In this study, we only partially removed the superior temporal gyrus (tissue width < 5 mm), so that the tissue could be isolated with less incision. A careful macroscopic examination was made to preserve arteries and veins while the incision was made, therefore the isolated lobe maintained a blood supply and survived. MRI scans of the two epileptic patients showed that the disconnected brain tissue still survived, the activity of temporal-parietal occipital nerve tissue was maintained, and nerve fibers were completely disconnected. The involved patients were followed-up for over 1 year after surgery, during which time the epilepsy was completely controlled.

The somatosensory system plays a crucial role in executing precise movements by providing sensory feedback (Farrer et al., 2003; Rabin and Gordon, 2004). Somatosensory dysfunction is a common problem following stroke. In particular, somatosensory impairments, such as impairment in touch, proprioception, light touch, and vibration have been frequently observed (Carey et al., 1993; Sullivan and Hedman, 2008; Tyson et al., 2008). Patients with somatosensory dysfunction show negative effects on motor control, and it sometimes becomes difficult to perform daily activities independently. In addition, these patients require more time to recover functions compared with those without somatosensory deficits (Doyle et al., 2010; Sommerfeld and von Arbin, 2004; Sullivan and Hedman, 2008). Therefore, a better understanding of the recovery mechanism underlying somatosensory dysfunction is necessary for a successful neurorehabilitation outcome.

Ischemic stroke is most commonly caused by vascular occlusion due to thrombosis or arterial embolism. Recently, thrombolysis has been used with increasing frequency for the treatment of acute ischemic stroke. Among the drugs used for thrombolysis, only recombinant tissue plasminogen activator is widely accepted internationally (Albers et al., 2008). In China, urokinase has been widely used for thrombolysis after acute ischemic stroke. Pro-urokinase is the precursor of urokinase. Compared with urokinase, pro-urokinase has greater ability to dissolve thrombus and is safer to use. A previous study found that the recanalization rate was significantly higher after arterial thrombolysis with pro-urokinase than with recombinant tissue plasminogen activator (Fischer et al., 2005). This study compared the thrombolytic effects of pro-urokinase, recombinant tissue plasminogen activator, and urokinase in a dog model of acute cerebral embolism. For each dog used, 10 mL of arterial blood was taken and placed at room temperature for 3 hours to allow natural consolidation. Blood clots were then pressed into a 2-mm diameter cylinder and cut into 2–3 mm lengths. After general anesthesia, dogs were fixed on an operating table and the trachea was intubated. A 5F sheathing canal was placed in the right femoral artery using a modified Seldinger method (Marx et al., 1996). The sheathing canal was advanced into the internal carotid artery guided by digital subtraction angiography. Vascular traveling to the anterior and middle cerebral arteries was observed in the anteroposterior view (Figure ​(Figure1A1A–C). A mixture of autologous blood clots and physiological saline was injected into the internal carotid artery using a 5 mL syringe. If no embolization was observed on digital subtraction angiography after the first injection of blood clots, the process was repeated (Takano et al., 1998; Oureshi et al., 2004; Harris et al., 2007). When anterior or middle cerebral artery embolization was confirmed, the sheathing canal was withdrawn. Digital subtraction angiography was repeated every 30 minutes for 3 hours to confirm embolization (Figure ​(Figure1D1D–F). Figure 1 Digital subtraction angiography images before and after treatment of acute cerebral embolism in dogs using pro-urokinase, recombinant tissue plasminogen activator, or urokinase. Stroke was successfully induced in 24 dogs. These 24 dogs were randomly divided into four groups: (1) Pro-urokinase group: 1.2 × 105 U/kg pro-urokinase was administered via the femoral vein. One-third of the pro-urokinase was dissolved in physiological saline and administered over 3 minutes, and the remainder was dissolved in 100 mL of physiological saline and administered over 30 minutes. (2) Recombinant tissue plasminogen activator group: 1.37 mg/kg of recombinant tissue plasminogen activator was administered via the femoral vein. One-tenth of the recombinant tissue plasminogen activator was administered over 1 minute, and the remainder was administered over 60 minutes. (3) Urokinase group: 2.15 × 106 U/kg urokinase was dissolved in 100 mL of physiological saline and administered by intravenous infusion over 30 minutes. (4) Model group: 100 mL of physiological saline was administered by intravenous infusion over 30 minutes. Digital subtraction angiography was performed every 30 minutes for 3 hours after thrombolysis. Based on assessment of the Thrombolysis In Myocardial Infarction flow grade, the recanalization rate was higher in the urokinase group than in the model group (Table 1, Figure ​Figure1G1G–U). Hematoxylin and eosin staining showed no hematoma in the infarcted area at 3 hours after thrombolysis in any of the groups, but nerve cells in the infarcted tissues showed degeneration, coagulative necrosis, vacuole-like structures, indistinct cell borders, and pyknotic or absent nuclei. In addition, the nerve cells and glial cells were obviously reduced in number or even absent. Infiltration of neutrophilic leukocytes and microglial proliferation or phagocytosis were observed in some regions. There were no obvious differences in cell apoptosis among the groups (Figure ​(Figure2A2A–E). Hemorrhage was observed in the infarcted area in one dog from each of the pro-urokinase and urokinase groups (Figure ​(Figure2F2F–H). Table 1 Effectiveness of pro-urokinase, recombinant tissue plasminogen activator, and urokinase for the treatment of acute cerebral embolism Figure 2 Histological findings in the area of cerebral infarction at 3 hours after thrombolysis (hematoxylin and eosin staining). Previous studies reported that patients who underwent thrombolysis over 3 hours had a high incidence of hemorrhage (Camerlingo et al., 2005). Obvious hematoma was not observed in this dog model of stroke because dogs have abundant collateral cerebrovascular circulation, resulting in a limited area of infarction, and thrombolysis was performed early. The results of this study show that recanalization after thromboembolism was similar after thrombolysis with pro-urokinase and recombinant tissue plasminogen activator, and that both these drugs were more effective than urokinase (both P < 0.05). However, pro-urokinase and recombinant tissue plasminogen activator did not have any definite protective effects against neuronal injury.