Preliminary guidelines for safe and effective use of repetitive transcranial magnetic stimulation in moderate to severe traumatic brain injury.

Transcranial magnetic stimulation has generated extensive interest within the traumatic brain injury (TBI) rehabilitation community, but little work has been done with repetitive protocols, which can produce prolonged changes in behavior. This is partly because of concerns about the safety of repetitive transcranial magnetic stimulation (rTMS) in subjects with TBI, particularly the risk of seizures. These risks can be minimized by careful selection of the rTMS protocol and exclusion criteria. In this article, we identify guidelines for safe use of rTMS in subjects with TBI based on a review of the literature and illustrate their application with a case study. Our subject is a 48-year-old man who sustained a severe TBI 5 years prior to beginning rTMS for the treatment of post-TBI depression. After a 4-week baseline period, we administered daily sessions of low-frequency stimulation to the right dorsolateral prefrontal cortex for 6 weeks. After stimulation, we performed monthly assessments for 3 months. The Hamilton Depression Rating Scale (HAMD) was our primary outcome measure. The stimulation was well tolerated and the patient reported no side effects. After 6 weeks of stimulation, the patient's depression was slightly improved, and these improvements continued through follow-up. At the end of follow-up, the patient's HAMD score was 49% of the average baseline score.

White matter abnormalities associated with disruptive behavior disorder in adolescents with and without attention-deficit/hyperactivity disorder.

Disruptive behavior disorders (DBD) are among the most commonly diagnosed mental disorders in children and adolescents. Some important characteristics of DBD vary based on the presence or absence of comorbid attention-deficit/hyperactivity disorder (ADHD), which may affect the understanding of and treatment decision-making related to the disorders. Thus, identifying neurobiological characteristics of DBD with comorbid ADHD (DBD+ADHD) can provide a basis to establish a better understanding of the condition. This study aimed to assess abnormal white matter microstructural alterations in DBD+ADHD as compared to DBD alone and healthy controls using diffusion tensor imaging (DTI). Thirty-three DBD (19 with comorbid ADHD) and 46 age-matched healthy adolescents were studied using DTI. Fractional anisotropy (FA), and mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) were analyzed using tract-based spatial statistics (TBSS). Significantly lower FA and higher MD, RD and AD in many white matter fibers were found in adolescents with DBD+ADHD compared to controls. Moreover, lower FA and higher RD were also found in the DBD+ADHD versus the DBD alone group. Alterations of white matter integrity found in DBD patients were primarily associated with ADHD, suggesting that ADHD comorbidity in DBD is reflected in greater abnormality of microstructural connections.

The interacting role of media violence exposure and aggressive-disruptive behavior in adolescent brain activation during an emotional Stroop task.

Only recently have investigations of the relationship between media violence exposure (MVE) and aggressive behavior focused on brain functioning. In this study, we examined the relationship between brain activation and history of media violence exposure in adolescents, using functional magnetic resonance imaging (fMRI). Samples of adolescents with no psychiatric diagnosis or with disruptive behavior disorder (DBD) with aggression were compared to investigate whether the association of MVE history and brain activation is moderated by aggressive behavior/personality. Twenty-two adolescents with a history of aggressive behavior and diagnosis of either conduct disorder or oppositional-defiant disorder (DBD sample) and 22 controls completed an emotional Stroop task during fMRI. Primary imaging results indicated that controls with a history of low MVE demonstrated greater activity in the right inferior frontal gyrus and rostral anterior cingulate during the violent word condition. In contrast, in adolescents with DBD, those with high MVE exhibited decreased activation in the right amygdala, compared with those with low MVE. These findings are consistent with research demonstrating the importance of fronto-limbic structures for processing emotional stimuli, and with research suggesting that media violence may affect individuals in different ways depending on the presence of aggressive traits.

Executive functioning characteristics associated with ADHD comorbidity in adolescents with disruptive behavior disorders.

The nature of executive dysfunction in youth with disruptive behavior disorders (DBD) remains unclear, despite extensive research in samples of children with attention-deficit hyperactivity disorder (ADHD). To determine the relationship between DBD, ADHD, and executive function deficits in aggressive teens, adolescents with DBD and comorbid ADHD (DBD + ADHD; n = 25), DBD without ADHD (DBD-ADHD; n = 23), and healthy controls (HC; n = 25) were compared on neurocognitive tests and questionnaires measuring executive functioning. Teens with DBD + ADHD performed worse on both neurocognitive and questionnaire measures of executive function than the DBD-ADHD and HC groups. Results suggest that subgroups of DBD may exist depending on the presence or absence of comorbid ADHD, which may have implications for the selection and efficacy of treatment strategies.

Magnetic resonance imaging findings in children with a first recognized seizure.

This study characterized structural abnormalities associated with onset of seizures in children, using magnetic resonance imaging and a standardized classification system in a large prospective cohort. Two hundred eighty-one children aged 6-14 years completed magnetic resonance imaging within 6 months of their first recognized seizure. Most examinations were performed with a standardized, dedicated seizure protocol; all were scored using a standard scoring system. At least one magnetic resonance imaging abnormality was identified in 87 of 281 (31%) children with a first recognized seizure. Two or more abnormalities were identified in 34 (12%). The commonest abnormalities were ventricular enlargement (51%), leukomalacia/gliosis (23%), gray-matter lesions such as heterotopias and cortical dysplasia (12%), volume loss (12%), other white-matter lesions (9%), and encephalomalacia (6%). Abnormalities defined as significant, or potentially related to seizures, occurred in 40 (14%). Temporal lobe and hippocampal abnormalities were detected at a higher frequency than in previous studies (13/87). Magnetic resonance imaging and a standardized, reliable, valid scoring system demonstrated a higher rate of abnormal findings than previously reported, including findings formerly considered incidental. Practice parameters may need revision, to expand the definition of significant abnormalities and support wider use of magnetic resonance imaging in children with newly diagnosed seizures.

Seizure recurrence risk following a first seizure in neurologically normal children.

PURPOSE: To define seizure recurrence rates in normal children who had had a single seizure and to define electroencephalography (EEG) or magnetic resonance imaging (MRI) utility in predicting seizure recurrence. METHODS: We studied 150 children (6 to 14 years) with a first afebrile, unprovoked seizure. Inclusion criteria were: Normal physical and neurological examination, undergone EEG and MRI studies of the brain, and followed for at least 27 months. These children participated in an ongoing prospective study of new onset seizures in childhood. RESULTS: The seizure recurrence rate was 66.4%. An abnormal EEG had no association with seizure recurrence at 9, 18, or 27 months (p = 0.1806, p = 0.2792, and p = 0.2379, respectively). A "significant" MRI abnormality, which occurred in 16.0% of patients, was associated with an increased seizure recurrence risk at 9 months (p = 0.0389) but not at 18 or 27 months. DISCUSSION: EEG findings poorly predict recurrence after a single seizure. The high rate of MRI abnormalities suggests that MRI may need consideration as a routine test to evaluate epilepsy in normal children.

The association of MRI findings and neuropsychological functioning after the first recognized seizure.

PURPOSE: To explore relationships between MRI abnormalities of the brain and neuropsychological functioning in children who were evaluated following their first recognized seizure. METHODS: Subjects were children aged 6 to 14 years with a first recognized seizure within the past 3 months who participated in a larger prospective study of child adaptation. The 249 children with neuropsychological testing and neuroimaging were studied. Children underwent neuropsychological examination an average of 2.8 months and MRI examination an average of 1.3 months after the first recognized seizure. On factor analysis four factors were found for neuropsychological function: LANG = Language, PS = Processing Speed, EC = Executive/ Construction, VMEM = Verbal Memory and Learning. For analysis, structural abnormalities found on MRI were classified as significant (yes/no) based on whether they were presumed to be related to the seizure condition. RESULTS: On MRI, 34 (14%) had structural abnormalities that were judged to be significant in that they were possibly related to their seizures. Children with significant abnormalities had significantly lower estimated IQ scores and significantly lower language, processing speed, executive/constructional ability, and verbal memory and learning factor scores than did children without significant abnormalities. CONCLUSIONS: Children who have structural brain abnormalities at onset have slightly lower cognitive functioning overall, and all neuropsychological domains seemed to be affected relatively equally. This pattern was apparent even when we restricted the analysis to children with intellectual functioning in the broadly normal range.

Magnetic resonance imaging (MRI) and electroencephalographic (EEG) findings in a cohort of normal children with newly diagnosed seizures.

In the initial assessment of children with new-onset seizures, the suggestion that electroencephalography (EEG) should be standard and that magnetic resonance imaging (MRI) should be optional has been questioned. The purposes of this study were to (1) describe the frequency of EEG and MRI abnormalities and (2) explore relationships between MRI and EEG findings to determine their relevance in the assessment of children with new-onset seizures who are otherwise developing normally. As part of an ongoing, prospective study of children with new-onset seizures, we studied 181 children (90 girls and 91 boys). Children were entered into the study within 3 months of their first-recognized seizure. The association between EEG and MRI abnormalities was explored using a chi-square test. Abnormal MRI findings were found in 32.6% (n = 59) of the sample. The EEG and MRI results agreed with respect to classification into normal or abnormal in 37% (n = 67). Of the 50 children with a normal EEG, however, 21 (42%) were found to have an abnormal MRI. We found an unexpectedly high frequency of imaging abnormalities in our sample of otherwise normal children, although the significance of these findings is not clear. Follow-up of these patients will help us interpret the importance of the abnormalities. Despite our relatively small sample, however, our findings indicate that a normal EEG does not reliably predict a normal MRI in children with first seizures.

A supervised method for calculating perfusion/diffusion mismatch volume in acute ischemic stroke.

Diffusion and perfusion (MR) imaging modalities identify overlapping but not identical areas of tissue as lesion following a stroke. It is thought that the 'mismatch' between modalities may represent tissue that could be recovered with proper (thrombolytic) treatment. We have designed a tool for semi-automated segmentation of the images and calculation of the mismatch volume. We present results from software phantoms and clinical data. Phantom results show our mismatch volume calculations are unbiased at realistic noise levels. Clinical data show that raters using our tool are consistent, fast (15min per subject) and indistinguishable from an expert using manual segmentation.

The effect of tumour type and distance on activation in the motor cortex.

Functional MRI has been widely used to identify the eloquent cortex in neurosurgical/radiosurgical planning and treatment of CNS neoplasms and malformations. In this study we examined the effect of CNS tumours on the blood oxygenation level-dependent (BOLD) activation maps in the primary and supplementary motor cortex. A total of 33 tumour patients and five healthy right-handed adults were enrolled in the study. Patients were divided into four groups based on tumour type and distance from primary motor cortex: (1) intra-axial, near, (2) extra-axial, near, (3) intra-axial, far and (4) extra-axial, far. The intra-axial groups consisted of patients with astrocytomas, glioblastomas and metastatic tumours of mixed histology; all the extra-axial tumours were meningiomas. The motor task was a bilateral, self-paced, finger-tapping paradigm. Anatomical and functional data were acquired with a 1.5 T GE Echospeed scanner. Maps of the motor areas were derived from the BOLD images, using SPM99 software. For each subject we first determined the activation volume in the primary motor area and the supplementary motor area (SMA) and then calculated the percentage difference between the hemispheres. Two factors influenced the activation volumes: tumour type (P<0.04) and distance from the eloquent cortex (P<0.06). Patients in group 1 (intra-axial, near) had the smallest activation area in the primary motor cortex, the greatest percentage difference in the activation volume between the hemispheres, and the largest activation volume in the SMA. Patients in group 4 (extra-axial, far) had the largest activation volume in the primary motor cortex, the least percentage difference in volume between the hemispheres, and the smallest activation volume in the SMA. There was no significant change in the volume of the SMA in any group, compared with controls, suggesting that, although there is a gradual decrease in SMA volume with distance from the primary motor area, the effect on motor reorganisation is minimal. All the tumour patients showed a net loss in total activation volumes (both hemispheres plus SMA) compared with controls. The effect of the tumours on interhemispheric volume differences was: group 1>group 3>group 2>group 4. Within the intra-axial tumours, there was no significant effect of tumour type on the results. We conclude that BOLD-imaged activation volume is affected at least by the interplay of two factors: tumour type and distance from the motor cortex. Further, all tumours may be expected to cause some loss of activation volumes in motor areas. We suggest that, with proper precautions and planning, BOLD functional magnetic resonance imaging (fMRI) maps can be useful in minimising damage to the functional areas.

Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study.

BACKGROUND: Functional imaging studies indicate that imbalances in cortico-limbic activity and connectivity may underlie the pathophysiology of MDD. In this study, using functional Magnetic Resonance Imaging (fMRI), we investigated differences in cortico-limbic activity and connectivity between depressed patients and healthy controls. METHODS: Fifteen unmedicated unipolar depressed patients and 15 matched healthy subjects underwent fMRI during which they first completed a conventional block-design activation experiment in which they were exposed to negative and neutral pictures. Next, low frequency blood oxygenation dependent (BOLD) related fluctuations (LFBF) data were acquired at rest and during steady-state exposure to neutral, positive and negative pictures. LFBF correlations were calculated between anterior cingulate cortex (ACC) and limbic regions--amygdala (AMYG), pallidostriatum (PST) and medial thalamus (MTHAL) and used as a measure of cortico-limbic connectivity. RESULTS: Depressed patients had increased activation of cortical and limbic regions. At rest and during exposure to neutral, positive, and negative pictures cortico-limbic LFBF correlations were decreased in depressed patients compared to healthy subjects. CONCLUSIONS: The finding of increased activation of limbic regions and decreased LFBF correlations between ACC and limbic regions is consistent with the hypothesis that decreased cortical regulation of limbic activation in response to negative stimuli may be present in depression.

Antidepressant effect on connectivity of the mood-regulating circuit: an FMRI study.

The mechanisms by which antidepressant-induced neurochemical changes lead to physiological changes in brain circuitry and ultimately an antidepressant response remain unclear. This study investigated the effects of sertraline, a selective serotonin reuptake inhibitor antidepressant, on corticolimbic connectivity, using functional magnetic resonance imaging (fMRI). In all, 12 unmedicated unipolar depressed patients and 11 closely matched healthy control subjects completed two fMRI scanning sessions at baseline and after 6 weeks. Depressed patients received treatment with sertraline between the two sessions. During each fMRI session, subjects first completed a conventional block-design experiment. Next, connectivity between cortical and limbic regions was measured using correlations of low-frequency blood oxygen level-dependent (BOLD) fluctuations (LFBF) during continuous exposure to neutral, positive, and negative pictures. At baseline, depressed patients had decreased corticolimbic LFBF correlations compared to healthy subjects during the resting state and on exposure to emotionally valenced pictures. At rest and on exposure to neutral and positive pictures, LFBF correlation between the anterior cingulate cortex and limbic regions was significantly increased in patients after treatment. However, on exposure to negative pictures, corticolimbic LFBF correlations remained decreased in depressed patients. The results of this study are consistent with the hypothesis that antidepressant treatment may increase corticolimbic connectivity, thereby possibly increasing the regulatory influence of cortical mood-regulating regions over limbic regions.

Cerebral activation patterns during working memory performance in multiple sclerosis using FMRI.

Working memory deficits are common in Multi Sclerosis (MS) and have been identified behaviourally in numerous studies. Despite recent advance in functional magnetic resonance imaging (fMRI), few published studies have examined cerebral activations associated with working memory dysfunction in MS. The present study examines brain activation patterns during performance of a working memory task in individual with clinically definite MS, compared to healthy controls (HC). fMRI was performed using a 1.5 Tesla GE scanner during a modified Paced Auditory Serial Addition Test (mPA-SAT). Participants were 6 individuals with MS with working memory impairment as evidenced on neuropsychological testing, 5 individuals with MS without working memory impairment, and 5 HC. Groups were demographically equivalent. Data were analyzed using Statistical Parametric Mapping (SPM99) software, with a stringent significance level (alpha < .005, voxel extent > or =8). Both MS groups and the HC group were able to perform the task, with comparable performance in terms of numbers of correct responses. Activation patterns within the HC and MS not-impaired groups were noted in similar brain regions, consistent with published observations in healthy samples That is, activations were lateralized to the left hemisphere, involving predominantly frontal regions. In contrast, the MS impaired group showed greater right frontal and right parietal lobe activation, when compared with the HC group. Thus, it appears that working memory dysfunction in MS is associated with altered patterns of cerebral activation that are related to the presence of cognitive impairement, and not solely a function of MS.

Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by the vagus nerves.

Women diagnosed with complete spinal cord injury (SCI) at T10 or above report vaginal-cervical perceptual awareness. To test whether the Vagus nerves, which bypass the spinal cord, provide the afferent pathway for this response, we hypothesized that the Nucleus Tractus Solitarii (NTS) region of the medulla oblongata, to which the Vagus nerves project, is activated by vaginal-cervical self-stimulation (CSS) in such women, as visualized by functional magnetic resonance imaging (fMRI). Regional blood oxygen level-dependent (BOLD) signal intensity was imaged during CSS and other motor and sensory procedures, using statistical parametric mapping (SPM) analysis with head motion artifact correction. Physiatric examination and MRI established the location and extent of spinal cord injury. In order to demarcate the NTS, a gustatory stimulus and hand movement were used to activate the superior region of the NTS and the Nucleus Cuneatus adjacent to the inferior region of the NTS, respectively. Each of four women with interruption, or "complete" injury, of the spinal cord (ASIA criteria), and one woman with significant, but "incomplete" SCI, all at or above T10, showed activation of the inferior region of the NTS during CSS. Each woman showed analgesia, measured at the fingers, during CSS, confirming previous findings. Three women experienced orgasm during the CSS. The brain regions that showed activation during the orgasms included hypothalamic paraventricular nucleus, medial amygdala, anterior cingulate, frontal, parietal, and insular cortices, and cerebellum. We conclude that the Vagus nerves provide a spinal cord-bypass pathway for vaginal-cervical sensibility in women with complete spinal cord injury above the level of entry into spinal cord of the known genitospinal nerves.

fMRI study of acupuncture-induced periaqueductal gray activity in humans.

BOLD fMRI was used to study acupuncture-induced activation (increase in the BOLD signal from undetectable) of the periaqueductal gray (PAG) and two somatosensory cortical areas in seven healthy human subjects. Mechanical stimulation (push-pull) was given to the LI4 (Hoku) acupoint or to a non-acupoint. The stimulation paradigm consisted of 5 runs, each consisting of four 30 s On/30 s OFF periods over 30 min. The scan for each ON period was analyzed individually. The PAG and cortical areas showed different activity patterns. PAG activity was episodic and reliably demonstrated after 20-25 min of stimulation; both cortical areas, however, were active > 90% of the time. Stimulation of a non-acupoint (leg) resulted in reduced levels of PAG and cortical activity.

Differential cerebellar activation on functional magnetic resonance imaging during working memory performance in persons with multiple sclerosis.

OBJECTIVE: To explore the potential role of the cerebellum in working memory dysfunction in multiple sclerosis (MS). DESIGN: Blood oxygen level dependent functional magnetic resonance imaging (fMRI) was used to examine cerebellar activation during a working memory task. SETTING: University-affiliated medical rehabilitation facility. PARTICIPANTS: Eight persons with MS and 5 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Change in hemodynamic response. fMRI data were acquired and subsequently analyzed by using Statistical Parametric Mapping. RESULTS: Both the control and MS groups showed significantly greater activations in the right cerebellar hemisphere as compared with the left side. Persons with MS, however, showed no detectable activations in 4 cerebellar substructures that were significantly active in controls (ie, right vermis, right dentate nucleus, right tonsil, cerebellar peduncle). CONCLUSIONS: The significantly decreased cerebellar activation in the MS group suggests that the cerebellum may play a role in the working memory impairment observed in MS.

Functional localization of brainstem and cervical spinal cord nuclei in humans with fMRI.

BACKGROUND AND PURPOSE: To our knowledge, no published functional map of the human lower brainstem exists. Our purpose was to use 1.5-T functional MR imaging (fMRI) to visualize the location of cranial nerve (CN) nuclei and other pontine, bulbar, and cervical spinal cord nuclei by using specific sensory stimulation or motor performance. METHODS: We localized nuclei by using cross-correlation analysis of regional blood oxygen level-dependent (BOLD) signal intensity during specific motor and sensory procedures based on known functions of specific nuclei. Statistical parametric mapping (SPM) analysis was used for comparison. Head, cardiac, and respiratory motion artifact correction was applied. Histologic atlases aided localization. RESULTS: We obtained evidence of localization of the following nuclei by using tests, as follows: main trigeminal sensory (CN V), brushing the face; abducens (CN VI), left-right eye movement; facial (CN VII), smiling and lip puckering; hypoglossal (CN XII), pushing the tongue against the hard palate; nucleus ambiguus, swallowing; nucleus tractus solitarii (NTS), tasting a sweet-sour-salty-bitter mixture; nucleus cuneatus, finger tapping; and cervical spinal cord levels C1-C3, tongue movement to activate the strap muscles. Activation of cortical motor and sensory areas and somatosensory thalamus corresponded with the tasks and sites of brainstem activation. Head movement was minimal, typically less than 1 mm in all three axes. CONCLUSION: With 1.5-T fMRI, the CN nuclei of the pons and medulla, and other nuclei of the lower brainstem and cervical spinal cord, can be localized in awake humans with specific sensory stimulation or motor performance.