Structural changes of central white matter tracts in Kennedy's disease - a diffusion tensor imaging and voxel-based morphometry study.

OBJECTIVES: Spinobulbar muscular atrophy [Kennedy's disease (KD)] is a rare X-linked neurodegenerative disorder of mainly spinal and bulbar motoneurons. Recent studies suggest a multisystem character of this disease. The aim of this study was to identify and characterize structural changes of gray (GM) and white matter (WM) in the central nervous system. MATERIAL AND METHODS: Whole-brain-based voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analyses were applied to MRI data of eight genetically proven patients with KD and compared with 16 healthy age-matched controls. RESULTS: Diffusion tensor imaging analysis showed not only decreased fractional anisotropy (FA) values in the brainstem, but also widespread changes in central WM tracts, whereas VBM analysis of the WM showed alterations primarily in the brainstem and cerebellum. There were no changes in GM volume. The FA value decrease in the brainstem correlated with the disease duration. CONCLUSION: Diffusion tensor imaging analysis revealed subtle changes of central WM tract integrity, while GM and WM volume remained unaffected. In our patient sample, KD had more extended effects than previously reported. These changes could either be attributed primarily to neurodegeneration or reflect secondary plastic changes due to atrophy of lower motor neurons and reorganization of cortical structures.

Long-term cognitive and emotional consequences of mild traumatic brain injury.

BACKGROUND: The objective of this study was to investigate long-term cognitive and emotional sequelae of mild traumatic brain injury (mTBI), as previous research has remained inconclusive with respect to their prevalence and extent. METHOD: Thirty-three individuals who had sustained mTBI on average 6 years prior to the study and 33 healthy control subjects were matched according to age, gender and education. Structural brain damage at time of testing was excluded by magnetic resonance imaging (MRI). A comprehensive neuropsychological test battery was conducted to assess learning, recall, working memory, attention and executive function. Psychiatric symptoms were assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Beck Depression Inventory (BDI). Possible negative response bias was ruled out by implementing the Word Memory Test (WMT). RESULTS: The mTBI individuals had significant impairments in all cognitive domains compared to the healthy control subjects. Effect sizes of cognitive deficits were medium to large, and could not be accounted for by self-perceived deficits, depression, compensation claims or negative response bias. BDI scores were significantly higher in the patient group, and three patients fulfilled DSM-IV criteria for a mild episode of major depression. CONCLUSIONS: Primarily, well-recovered individuals who had sustained a minor trauma more than half a decade ago continue to have long-term cognitive and emotional sequelae relevant for everyday social and professional life. mTBI may lead to a lasting disruption of neurofunctional circuits not detectable by standard structural MRI and needs to be taken seriously in clinical and forensic evaluations.

Neural correlates of trait anxiety in fear extinction.

BACKGROUND: Fear conditioning involves the amygdala as the main neural structure for learning fear responses whereas fear extinction mainly activates the inhibitory prefrontal cortex (PFC). In this study we investigated whether individual differences in trait anxiety affect amygdala and dorsal anterior cingulate cortex (dACC) activation during fear conditioning and extinction. METHOD: Thirty-two healthy subjects were investigated by functional magnetic resonance imaging (fMRI) at 3 T while performing a cued fear-conditioning task. All participants completed the trait version of the State-Trait Anxiety Inventory (STAI-T). Activations of the amygdala and the dACC were examined with respect to the effects of trait anxiety. RESULTS: Analysis of the fMRI data demonstrated enhanced activation in fear-related brain areas, such as the insula and the ACC, during both fear conditioning and extinction. Activation of the amygdala appeared only during the late acquisition phase whereas deactivation was observed during extinction. Regression analyses revealed that highly trait-anxious subjects exhibited sustained amygdala activation and reduced dACC involvement during the extinction of conditioned responses. CONCLUSIONS: This study reveals that high levels of trait anxiety are associated with both increased amygdala activation and reduced dACC recruitment during the extinction of conditioned fear. This hyper-responsivity of the amygdala and the deficient cognitive control during the extinction of conditioned fear in anxious subjects reflect an increased resistance to extinct fear responses and may thereby enhance the vulnerability to developing anxiety disorders.

Pattern and progression of white-matter changes in a case of posterior cortical atrophy using diffusion tensor imaging.

BACKGROUND: The progression of white-matter changes in a case of posterior cortical atrophy (PCA) was examined over a period of 15 months using diffusion tensor imaging (DTI) and the association with neuropsychological variables was studied. PATIENT AND METHODS: A PCA patient was observed over a period of 15 months. DTI and volumetric magnetic resonance imaging were obtained at visit 1 and 15 months later. Fractional anisotropy (FA) and volumetric changes were compared with findings in a typical case of Alzheimer disease (AD) and in 65 healthy volunteers, and the association of neuropsychological deficits with these changes was studied. RESULTS: Reduction in FA was focused on the occipital lobe in the early stages of PCA. During the 15-month period, the FA values of the PCA patient tended to align with the FA ratios of the AD patient, with a more pronounced FA reduction in the parietal lobes, as opposed to a stable FA level in the occipital lobe. In addition to the DTI changes, clinical and neuropsychological symptoms deteriorated further. Brain volumes (grey matter, white matter and total normalised brain volume) of the PCA patient were substantially decreased compared with the control group, but loss of tissue volumes showed only marginal progression between visit 1 and 2. CONCLUSIONS: The findings suggest that PCA starts as distinct clinical syndrome but in its later course might turn into a final pathway shared with AD. DTI might be helpful in detecting changes in cerebral white matter during disease progression in PCA patients.

Functional anatomy of visuo-spatial working memory during mental rotation is influenced by sex, menstrual cycle, and sex steroid hormones.

Recent observations indicate that sex and level of steroid hormones may influence cortical networks associated with specific cognitive functions, in particular visuo-spatial abilities. The present study probed the influence of sex, menstrual cycle, and sex steroid hormones on 3D mental rotation and brain function using 3-T fMRI. Twelve healthy women and 12 men were investigated. Menstrual cycle and hormone levels were assessed. The early follicular and midluteal phase of the menstrual cycle were chosen to examine short-term cyclical changes. Parietal and frontal areas were activated during mental rotation in both sexes. Significant differences between men and women were revealed in both phases of menstrual cycle. In men we observed a significant correlation of activation levels with testosterone levels in the left parietal lobe (BA 40). In women, a cycle-dependent correlation pattern was observed for testosterone: brain activation correlated with this male hormone only during the early follicular phase. In both cycle phases females' brain activation was significantly correlated with estradiol in frontal and parietal areas. Our study provides evidence that fMRI-related activity during performance of cognitive tasks varies across sex and phases of the menstrual cycle. The variation might be partly explained by better task performance in men, but our results indicate that further explanations like basic neuronal or neurovascular effects modulated by steroid hormones must be considered. Both estradiol and testosterone levels may influence fMRI signals of cognitive tasks, which should affect selection of subjects for future fMRI studies.

Functional activity within brain tumors: a magnetic source imaging study.

OBJECTIVE: To determine whether low-grade gliomas contain functional cortical activity more often than high-grade gliomas within radiologically defined abnormal tissue. METHODS: Patients with intra-axial cerebral lesions located in the vicinity of eloquent brain cortex preoperatively underwent magnetic source imaging. A dual 37-channel biomagnetometer was used to perform the imaging. Evoked magnetic fields were analyzed using the single-equivalent dipole representation to ascertain the neuronal source. Stimuli included painless tactile somatosensory stimulation of fingers, toes, and lips and auditory presentation of pure sinusoidal tones. RESULTS: A retrospective analysis of 106 nonconsecutively treated patients, who had undergone preoperative magnetic source imaging between February 1996 and December 1999, revealed that 24.5% of the patients had been at risk for neurological deficits, because functionally active tissue was located within or at the border of the tumor. Functional activity was found within the radiologically defined lesion in 18% of Grade 2 tumors, in 17% of Grade 3 tumors, and in 8% of Grade 4 tumors. CONCLUSION: The results confirm that, regardless of tumor grade, intra-axial brain tumors may involve or directly border on functional cortex. The degree of involvement of functionally viable cortex appeared greater for low-grade tumors than for high-grade lesions. On the other hand, high-grade lesions were more likely to be associated with functional cortex at their margins or within peritumoral edema. To safely maximize tumor resection, preoperative functional imaging and intraoperative electrophysiological mapping of the cerebral cortex and the white matter tracts are deemed necessary.

Changes of pituitary gland volume in Kennedy disease.

BACKGROUND AND PURPOSE: Kennedy disease is a rare X-linked neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the androgen-receptor gene. Apart from neurologic signs, this mutation can cause a partial androgen insensitivity syndrome with typical alterations of gonadotropic hormones produced by the pituitary gland. The aim of the present study was therefore to evaluate the impact of Kennedy disease on pituitary gland volume under the hypothesis that endocrinologic changes caused by partial androgen insensitivity may lead to morphologic changes (ie, hypertrophy) of the pituitary gland. MATERIALS AND METHODS: Pituitary gland volume was measured in sagittal sections of 3D T1-weighted 3T-MR imaging data of 8 patients with genetically proven Kennedy disease and compared with 16 healthy age-matched control subjects by use of Multitracer by a blinded, experienced radiologist. The results were analyzed by a univariant ANOVA with total brain volume as a covariant. Furthermore, correlation and linear regression analyses were performed for pituitary volume, patient age, disease duration, and CAG repeat expansion length. Intraobserver reliability was evaluated by means of the Pearson correlation coefficient. RESULTS: Pituitary volume was significantly larger in patients with Kennedy disease (636 [±90] mm(3)) than in healthy control subjects (534 [±91] mm(3)) (P = .041). There was no significant difference in total brain volume (P = .379). Control subjects showed a significant decrease in volume with age (r = -0.712, P = .002), whereas there was a trend to increasing gland volume in patients with Kennedy disease (r = 0.443, P = .272). Gland volume correlated with CAG repeat expansion length in patients (r = 0.630, P = .047). The correlation coefficient for intraobserver reliability was 0.94 (P < .001). CONCLUSIONS: Patients with Kennedy disease showed a significantly higher pituitary volume that correlated with the CAG repeat expansion length. This could reflect hypertrophy as the result of elevated gonadotropic hormone secretion caused by the androgen receptor mutation with partial androgen insensitivity.

Closed traumatic brain injury model in sheep mimicking high-velocity, closed head trauma in humans.

To date, there are only a few, non-evidence based, cerebroprotective therapeutic strategies for treatment and, accordingly, for prevention of secondary brain injuries following severe closed head trauma. In order to develop new therapy strategies, existing realistic animal models need to be advanced. The objective is to bridge standardized small animal models and actual patient medical care, since the results of experimental small animal studies often cannot be transferred to brain-injured humans. For improved standardization of high-velocity trauma, new trauma devices for initiating closed traumatic brain injury in sheep were developed. The following new devices were tested: 1. An anatomically shaped rubber bolt with an integrated oscillation absorber for prevention of skull fractures; 2. Stationary mounting of the bolt to guarantee stable experimental conditions; 3. Varying degrees of trauma severity, i. e., mild and severe closed traumatic brain injury, using different cartridges; and 4. Trauma analysis via high-speed video recording. Peritraumatic measurements of intracranial pressure, brain tissue pH, brain tissue oxygen, and carbon dioxide pressure, as well as neurotransmitter concentrations were performed. Cerebral injuries were documented with magnetic resonance imaging and compared to neuropathological results. Due to the new trauma devices, skull fractures were prevented. The high-speed video recording documented a realistic trauma mechanism for a car accident. Enhancement of extracellular glutamate, aspartate, and gamma amino butyric acid concentrations began 60 min after the trauma. Magnetic resonance imaging and neuropathological results showed characteristic injury patterns of mild, and severe, closed traumatic brain injury. The severe, closed traumatic brain injury group showed diffuse axonal injuries, traumatic subarachnoid hemorrhage, and hemorrhagic contusions with inconsistent distribution among the animals. The model presented here achieves a gain in standardization of severe, closed traumatic brain injury by increasing approximation to reality. The still existent heterogeneity of brain pathology mimics brain changes observed in patients after high-energy trauma. This model seems to close the gap between experimental small animal models and clinical studies. However, further investigations are needed to evaluate if this model can be used for testing new therapeutic strategies for these patients.

Nerve fiber impairment of anterior thalamocortical circuitry in juvenile myoclonic epilepsy.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is a syndrome of idiopathic generalized epilepsy (IGE) without structural brain abnormalities detectable by MRI or CT. OBJECTIVE: In the present study, we addressed the question of whether diffusion tensor MRI (DTI) can detect disease-specific white matter (WM) abnormalities in patients with JME. METHODS: We performed whole head DTI at 3 T in 10 patients with JME, 8 age-matched patients with cryptogenic partial epilepsy (CPE), and 67 age-matched healthy volunteers. Nerve fiber integrity was compared between the groups on the basis of optimized voxel-by-voxel statistics of fractional anisotropy (FA) maps obtained by DTI (analysis of covariance, categorical factor "group," covariate "age"). RESULTS: FA was reduced in a WM region associated with the anterior thalamus and prefrontal cortex in patients with JME compared to both control subjects and patients with CPE (p < 0.001). The patients with CPE showed normal values in this particular WM region. The FA reductions in the patients with JME correlated with the frequency of generalized tonic-clonic seizures (Spearman R = 0.54, p = 0.05). No significant correlations were found in the JME sample between FA reduction and the duration of antiepileptic medication. CONCLUSIONS: The results support the hypothesis that juvenile myoclonic epilepsy is associated with abnormalities of the thalamocortical network that can be detected by diffusion tensor MRI.

Relevance of image fusion for target point determination in functional neurosurgery.

BACKGROUND: For the treatment of medically refractory movement disorders such as Parkinson's disease, essential tremor and primary dystonia, deep brain stimulation (DBS) has become one of the main treatment options. The targets for implantation of the stimulation electrodes are various nuclei within the basal ganglia or the thalamic and subthalamic area. Accurate target localisation is of major importance for outcome and patient safety. The goal of this study was to evaluate the role of image fusion in the determination of target co-ordinates. METHOD: We conducted a retrospective study on 10 patients in whom 17 DBS electrodes had been implanted. Coordinates of the anterior and posterior commissures and of the DBS targets were compared on pre- and postoperative computerised tomography (CT) and fused CT/magnetic resonance scans. The targets as defined on the images were further compared with the targets derived intra-operatively with microelectrode recordings (MER) and macrostimulation. FINDINGS: The achievable mean target accuracy was of the order of the diameter of the DBS electrode and of the accuracy of the image fusion algorithm, i.e. about 1 mm. However, the maximal differences were between 1.8 mm and 3.2 mm. INTERPRETATION: Image fusion is a helpful tool for accurate determination of target point co-ordinates in DBS. In combination with intraoperative, electrophysiological recordings and stimulation which are still considered to be the most reliable localisation methods, image fusion may help to discern the anatomical and functional three-dimensionality of the target nuclei. Image fusion may reduce the number of trajectories needed for intraoperative electrophysiological determination of the optimal electrode localisation and thus lower the risk of complications.

Anatomy of the cerebral ventricular system for endoscopic neurosurgery: a magnetic resonance study.

BACKGROUND: Endoscopy has developed into an integral part of minimally invasive neurosurgery. For further technological innovations, detailed knowledge about the pathological anatomy is essential. The gross anatomy of the cerebral ventricular system has been meticulously investigated with ventriculography and casts. Extensive volumetric measurements based on neuroradiological images have been performed, but only little is known about the surgically relevant linear distances in patients with hydrocephalus. METHOD: Thirty healthy volunteers and thirty patients suffering from hydrocephalus were scanned with high-resolution 3-D magnetic resonance imaging sequences. The image volumes were sliced identically with the help of Siemens Prominence software. Individual anatomical measurements of the ventricular system were carried out, mean values and standard deviations were calculated, and different endoscopic approaches were investigated. FINDINGS: In healthy volunteers the measurements confirmed the results obtained from ventriculography and anatomic casts. In hydrocephalic patients the ventricular system was found to be enlarged asymmetrically. The optimal neuroendoscopic approach showed considerable, interindividual variation. INTERPRETATION: This 3-D magnetic resonance imaging study revealed surgically and clinically relevant aspects of the pathologic anatomy of hydrocephalic patients, in comparison to healthy volunteers. Individualized planning of the endoscopic approach appears to be warranted. Finally, the data provided a sound basis for the further development of neuroendoscopes.

Versatile intraoperative MRI in neurosurgery and radiology.

BACKGROUND: Several models for the application of intra-operative magnetic resonance imaging (IMRI) have recently been reported, most of them unique. Two fundamental issues need to be addressed: optimal use of the scanner to ensure a wide base for research, development and clinical application, and an organisational model that facilitates such use. METHOD: While in our setting the IMRI project was initiated by the neurosurgeons, the need for wider use of the facilities was recognised since the beginning of the planning phase in 1996. An organisational model was developed that allowed for development of neurosurgical applications, radiological imaging, and radiological interventions and for the research and development work of the vendor. A resistive 0.23 T MR scanner was installed in a dedicated operating room environment. Unique to this scanner is the ability to turn off the magnet, allowing for normal OR activities and devices, and to turn on the magnet as needed with a relatively short six-minute ramp up time. A staged surgical technique was perfected, allowing for transfer of data to the neuronavigator outside the scanner during surgery. In neurosurgery, IMRI was used as one part of a neuronavigational system that included ultrasound imaging, intra-operative cortical stimulation during awake procedures, electrocorticography and two neuronavigators. FINDINGS: 34 neurosurgical cases included 27 brain tumour resections, 5 brain tumour biopsies, 1 extirpation of an arterio-venous malformation, and 1 haematoma evacuation. The scanner could also be used for normal clinical imaging where obese patients, children, claustophobic patients and postoperative control examinations were the major groups. The radiologists performed 110 interventions, including bone and abdominal biopsies, nerve root infiltrations and local pain therapies, with the optical needle tracking system under continuous MRI guidance. The organisational model allowed frequent use of the facilities for both neurosurgery and radiology and continuous development of the facilities. Intra-operative ultrasound was used in 20 tumour resections and in two open brain biopsies. This resulted in reduction of the number of MR imaging sessions during surgery. Five of the 27 resections were performed as awake craniotomies with cortical stimulation. For two of the resections, electrocorticography and depth electrode registrations were used. Furthermore, various non-MRI-compatible instruments and devices were used. INTERPRETATION: Intra-operative MRI is an imaging tool that can be useful especially in the context of neuronavigation. A scanner that can be turned off during surgery is particularly appropriate for neurosurgery. The concept of joint use of such facilities with other clinicians is mutually worthwhile.

Registration in interventional procedures with optical navigator.

Performing interventional procedures in the close proximity to an MR scanner widens the range of operations available for an optical tracking system. In order to gain the full benefits from both unrestricted use of surgical instruments outside the magnet and intraoperative imaging, a method for transferring the registration data of the optical navigator between two locations is required. An optical tracking system, which provides such a transfer method and tracks patient position during a surgical procedure, has been developed, tested, and demonstrated with two patient cases. J. Magn. Reson. Imaging 2001;13:93-98.