Changes in brain morphology in patients with obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is a common disease that leads to daytime sleepiness and cognitive impairment. Attempts to investigate changes in brain morphology that may underlie these impairments have led to conflicting conclusions. This study was undertaken to aim to resolve this confusion, and determine whether OSA is associated with changes in brain morphology in a large group of patients with OSA, using improved voxel-based morphometry analysis, an automated unbiased method of detecting local changes in brain structure. METHODS: 60 patients with OSA (mean apnoea hypopnoea index 55 (95% CI 48 to 62) events/h, 3 women) and 60 non-apnoeic controls (mean apnoea hypopnoea index 4 (95% CI 3 to 5) events/h, 5 women) were studied. Subjects were imaged using T1-weighted 3-D structural MRI (69 subjects at 1.5 T, 51 subjects at 3 T). Differences in grey matter were investigated in the two groups, controlling for age, sex, site and intracranial volume. Dedicated cerebellar analysis was performed on a subset of 108 scans using a spatially unbiased infratentorial template. RESULTS: Patients with OSA had a reduction in grey matter volume in the right middle temporal gyrus compared with non-apnoeic controls (p<0.05, corrected for topological false discovery rate across the entire brain). A reduction in grey matter was also seen within the cerebellum, maximal in the left lobe VIIIb close to XI, extending across the midline into the right lobe. CONCLUSION: These data show that OSA is associated with focal loss of grey matter that could contribute to cognitive decline. Specifically, lesions in the cerebellum may result in both motor dysfunction and working memory deficits, with downstream negative consequences on tasks such as driving.

Relationship between language lateralization and handedness in left-hemispheric partial epilepsy.

OBJECTIVE: To investigate the relationship between language lateralization and handedness in patients with epilepsy and a left-sided seizure focus and in healthy control subjects. METHODS: We recruited a consecutive series of 74 patients and 70 control subjects. Functional MRI, using a noun-verb generation task, was performed to establish the language laterality index (LI). Handedness was quantified using the Edinburgh Handedness Inventory. RESULTS: Patients showed a shift toward atypical language lateralization (0.43 +/- 0.47; controls 0.57 +/- 034; p < or = 0.05) and left-handedness (55 +/- 57; controls 74 +/- 39; p < or = 0.05). The LI and handedness were correlated in patients (r = 0.54; F = 25.9; p < 0.001) but not in control subjects (r = 0.1; F = 0.64; NS). A combination of left-handedness and atypical LI was more frequent in patients (12%) than control subjects (0%; p < or = 0.05). Crossed hemispheric specialization (e.g., right-handedness associated with atypical LI) was equally frequent in patients (20%) and control subjects (16%; NS). CONCLUSION: In epilepsy patients with a left-sided seizure focus, language lateralization is correlated to handedness. The increased frequency of left-handedness and associated atypical language lateralization is most likely related to the left-hemispheric seizure focus, influencing hemispheric specialization for both domains.

Pathologic and physiologic function in the subcortical band of double cortex.

Double cortex is a neuronal migration disorder, associated with impaired cognitive function and seizures, and characterized by a subcortical band of neurons. Using functional MRI, we assessed the involvement of the subcortical band in language function and with interictal discharges. In both girls assessed, language-associated activation was in typical cortical areas, as well as in parts of the subcortical band. Interictal discharges were associated with deactivation in the subcortical band. This suggests involvement of the subcortical neurons in physiologic and pathologic functions.

Typical childhood absence seizures are associated with thalamic activation.

Functional MRI with simultaneously acquired EEG (fMRI/EEG) can identify areas of signal change associated with interictal discharges. We report the fMRI/EEG study of a child with newly-diagnosed IGE, performed prior to the start of antiepileptic medication. The 7-years-old girl had very frequent absences, associated with eyelid myoclonia. Her EEG showed frequent, typical 3/sec discharges. Functional MRI was performed with a 3T scanner using whole brain gradient echo-planar imaging, and the EEG was recorded with 18, non-metallic, scalp electrodes. Ten bursts of generalized discharges were captured during 30 minutes fMRI/EEG acquisition. The bursts lasted 3.4 (SD +/- 0.6) seconds. Event-related analysis was performed with SPM2 and iBrain software. Functional MRI showed prominent, bilateral thalamic activation, and less pronounced areas of cortical activation and deactivation. This study demonstrates thalamic activation in typical, untreated childhood absence epilepsy. The cortical signal change may be related to a thalamo-cortical circuit.

Structural abnormalities remote from the seizure focus: a study using T2 relaxometry at 3 T.

OBJECTIVE: To determine the extent and severity of mesial temporal and subcortical signal abnormalities in patients with partial epilepsy. METHODS: T2 relaxation time maps were acquired in 50 consecutive patients and 55 control subjects on a 3 T MRI scanner. Twenty-two patients had hippocampal sclerosis (HS), 16 had malformations of cortical development (MCD), and 12 had no obvious MR abnormalities (normal MR). The following eight regions were measured bilaterally: hippocampus, anterior temporal lobe (ATL) white matter, amygdala, frontal lobe white matter, caudate, putamen, pallidum, and thalamus. RESULTS: In patients with HS, increased T2 relaxation times were found in the ipsilateral hippocampus and ATL but not in subcortical nuclei. In patients with MCD, increased T2 relaxation times were found in the temporal lobe (hippocampus, ATL) and in subcortical areas (caudate, putamen, and pallidum); in patients with normal MR, increased T2 relaxation times were found in the hippocampus and putamen. The degree of abnormality did not correlate with the duration of epilepsy or the estimated seizure load. CONCLUSIONS: Mesial temporal structures show increased T2 relaxation times not only in patients with hippocampal sclerosis but also in patients with a seizure focus remote from the hippocampus. Patients with normal MR and focal malformations of cortical development have increased T2 relaxation times in subcortical structures. Therefore, abnormalities in T2 relaxation time can be found remote from the seizure focus. They cannot be simply attributed to secondary seizure effects.

Language cortex activation in normal children.

OBJECTIVE: To describe a protocol for use in young children and adolescents for determining language representation. METHODS: We performed 130 fMRI studies in 48 children and 17 adults. Verb generation (VG) and orthographic lexical retrieval (OLR) were used. The localization and lateralization of activation was rated visually. Regional voxel counts measured asymmetry and extent of activation. RESULTS: Activation was predominantly left-lateralized (children 85%, adults 94%), and there was no difference in the localization of activation for either paradigm. Children's typical sites of activation included mesial (96%), inferior (94%) and middle frontal (92%) gyri, the inferior (85%) and superior (65%) temporal cortex, and the cerebellum (67%). Less frequently activated sites were insular (50%) and posterior parietal (48%) cortices. Quantitative asymmetry index scores and visual inspection of laterality were concordant. Greater quantitative asymmetry for VG than OLR occurred in children. Laterality was not related to age, sex, task proficiency, or handedness. Frontal region voxel counts lower in children than adults and left sided counts correlated with task proficiency. CONCLUSIONS: Language fMRI can be performed in young children using resources available to clinical centers. The similarity in frequency of left language lateralization between children and adults suggests that language representation establishes early in development. The reduced amount of frontal region of interest activation in task-specific regions in children may reflect different levels of ability. However, the left-right distribution of activation does not appear to depend on task performance or age. These normative data provide a basis for decisions about language laterality in pediatric patients.

Spike-triggered fMRI in reading epilepsy: involvement of left frontal cortex working memory area.

OBJECTIVE: To determine the origin of epileptiform activity in reading epilepsy (RE) and the association between these regions and regions activated by reading, and to assess brain morphometry in these areas. METHODS: In two subjects with RE, EEG was recorded inside the three tesla MRI while subjects read silently. Spike-triggered fMRI images were compared to baseline. In a second fMRI study, 30 seconds of silent reading was compared to visual fixation. Morphometry of these areas was assessed using curvilinear surface reconstruction. Left central sulcal patterns in three subjects with RE were compared to three subjects with idiopathic generalized epilepsy (IGE) and 12 normal controls. RESULTS: One subject with RE showed spike-related activity (17 spikes) in the left precentral gyrus, and bilaterally in the central sulcus and globus pallidus. The other showed no definite activation owing to low spike numbers (4 spikes). In both subjects, the block reading task recruited normal visual and language areas including the left posterior middle frontal gyrus. Two subjects with RE showed an unusual gyrus branching anteriorly off the left central sulcus. A similar sulcal pattern was seen in none of the subjects with IGE and only 1 of 12 controls. CONCLUSION: Spike activity overlapped with reading activity in the left middle frontal gyrus, a structure recruited during working memory cognitive tasks. The authors postulate that, because of a local structural anomaly, the spikes of reading epilepsy spread from working memory areas into adjacent motor cortex, activating a cortical subcortical circuit.

Reemergence of activation with poststroke somatosensory recovery: a serial fMRI case study.

The authors demonstrate the potential for poststroke return of activation in regions normally involved in touch discrimination in a serial, whole-brain fMRI study of a patient with marked sensory loss followed by good recovery. A return of activation in ipsilesional primary and bilateral secondary somatosensory cortices was observed at 3 months after stroke and was maintained at 6 months, indicating a reemergence of activation after the interval of somatosensory recovery. There was little evidence of neural plastic changes early after stroke (2 weeks), when sensory loss was severe.

Brain reorganisation in cerebral palsy: a high-field functional MRI study.

Early brain damage may induce alternative organisation of cortical brain functions. This may happen even if there is no damage to the cortex. We assessed a 15-year-old girl with a perinatal left-sided subcortical lesion without cortical damage by functional MRI at 3 Tesla. The patient had congenital hemiparesis, mirrored limb movements and normal language function. Functional MRI was used to assess language using orthographic-lexical retrieval and noun-verb generation tasks, and demonstrated right-sided language dominance. Functional MRI of motor function was assessed for both hands separately, by squeezing a rubber balloon. Both hand movements induced asymmetric bilateral activation of the motor cortex, with a predominance of contralateral activation. Language-associated activity is usually left-hemispheric, but was found in the undamaged right-sided hemisphere. Motor function was associated with the unusual pattern of bilateral cortical activation. The MR findings explain the clinical features and suggest widespread alternative cortical organisation in the presence of a focal lesion confined to subcortical structures.

A neurocognitive account of frontal lobe involvement in orthographic lexical retrieval: an fMRI study.

The present study aimed to examine the relationship between activation induced by an orthographic lexical retrieval (OLR) task and performance across time on the standard clinical version of OLR, the Controlled Oral Word Association Test (COWAT). The number of significantly activated pixels in a frontal lobe region of interest (encompassing middle and inferior frontal gyri) were measured for the left and right cerebral hemispheres in 20 volunteers. A relationship between the pixel count and the total number of words retrieved during the COWAT was found for the left but not the right hemisphere. Further examination of the left-sided relationship showed that the number of pixels in the left middle frontal region of interest correlated significantly with the second, but not the first, 30-s COWAT epoch. By contrast, the first epoch, but not the second, correlated significantly with the pixel count within the left inferior frontal region of interest. These relationships suggest differential involvement of dorsolateral and ventrolateral prefrontal cortex in specific cognitive processes fundamental to the production of language. Interindividual variation in activation levels may reflect underlying differences in cognitive processing capacity. This study is the first attempt to examine the relationship between fMRI activation and standard verbal fluency performance.

Prediction of the final infarct volume within 6 h of stroke using single photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime.

BACKGROUND: A simple method to predict the final infarct volume within 6 h of onset of hemispheric ischemic stroke based on the measurement of cerebral blood flow (CBF) using single photon emission computed tomography (SPECT) with techneticum-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO) was investigated in a clinical model involving patients without definite early reperfusion or clinical recovery. METHODS: A group of 16 patients (group 1) was used to establish the methodology, which was then validated in a second group of 14 patients (group 2). The final infarct volume was defined using computed tomography (CT) performed at least 7 days after stroke. The relative CBF threshold value, expressed as a percentage of the mean contralateral hemispheric value, which most closely estimated the final infarct size on coregistered CT was established for each patient. RESULTS: The mean threshold CBF value for group 1 was 63.7%. When this value was used to predict infarct size in group 2, a close correlation was observed between the actual and the estimated sizes (r = 0.973, p < 0.0001). This value was not time dependent. CONCLUSIONS: If no significant early reperfusion or clinical recovery occurs, a CBF threshold value of 63.7% on (99m)Tc-HMPAO SPECT performed within 6 h of stroke onset will reliably predict the final infarct size.

The fate of hypoxic tissue on 18F-fluoromisonidazole positron emission tomography after ischemic stroke.

We studied 24 patients up to 51 hours after ischemic stroke using 18F-fluoromisonidazole positron emission tomography to determine the fate of hypoxic tissue likely to represent the ischemic penumbra. Areas of hypoxic tissue were detected on positron emission tomography in 15 patients, and computed tomography was available in 12 patients, allowing comparison with the infarct volume to determine the proportions of the hypoxic tissue volume that infarcted and survived. The proportion of patients with hypoxic tissue and the amount of hypoxic tissue detected declined with time. On average, 45% of the total hypoxic tissue volume survived and 55% infarcted. Up to 68% (mean, 17.5%) of the infarct volume was initially hypoxic. Most of the tissue "initially affected" proceeded to infarction. We correlated hypoxic tissue volumes with neurological and functional outcome assessed using the National Institutes of Health Stroke Scale, Barthel Index, and Rankin Score. Initial stroke severity correlated significantly with the "initially affected" volume, neurological deterioration during the first week after stroke with the proportion of the "initially affected" volume that infarcted, and functional outcome with the infarct volume. Significant reductions in the size of the infarct and improved clinical outcomes might be achieved if hypoxic tissue can be rescued.

The functional neuroanatomy and long-term reproducibility of brain activation associated with a simple finger tapping task in older healthy volunteers: a serial PET study.

We examined long-term reproducibility of the functional organization of the brain associated with a simple finger tapping movement using positron emission tomography (PET). Repeat measurements of regional cerebral blood flow were obtained in 10 individuals, ages 35 to 82 years (mean 52 years), at scanning sessions separated by 6 months. Although the functional neuroanatomy of hand movements has previously been investigated with PET by a number of groups, none has reported systematic investigation of the consistency of brain activation over an extended time. As expected, we found significant activation in the left precentral gyrus [Talairach coordinate (-32, -34, 52)], postcentral gyrus (-22, -48, 56), and supplementary motor area (SMA) (-2, -18, 52) at the initial study, consistent with previous studies in younger subjects. For the follow-up study we also found significant activation in the left precentral (-36, -28, 52) and postcentral (-28, -36, 52) gyri and in the SMA (2, -16, 56). Our group results demonstrate consistent anatomical location and extent of motor activation over time. More importantly, analysis of individuals confirmed the presence of consistent sites of activation in primary sensorimotor cortex and SMA over the 6-month interval in most subjects. A high degree of consistency in location of activation in the group, and within individuals, over time suggests that changes in loci of activation may be confidently monitored using the PET method. Evidence of individual differences in extent of activation over time highlights the need for caution when interpreting similar changes in patient studies.

No evidence of hypoxic tissue on 18F-fluoromisonidazole PET after intracerebral hemorrhage.

We studied six patients after intracerebral hemorrhage (ICH) and eight controls using positron emission tomography (PET) with to determine whether a zone of tissue hypoxia, possibly representing "penumbral" tissue, exists surrounding an intracerebral hemorrhage. None of the stroke patients, studied 24 to 43 hours after symptom onset, nor any of the controls exhibited areas of tissue hypoxia on 18F-fluoromisonidazole PET images. These findings may have implications for the treatment of intracerebral hemorrhage with neuroprotective strategies.

Motor cortex localization using functional MRI and transcranial magnetic stimulation.

OBJECTIVE: Congenital brain lesions producing focal seizures may be accompanied by reorganization of the areas responsible for motor and sensory functions within the brain due to a phenomenon that has been termed "neuronal plasticity." This can be studied using functional MRI (fMRI) and transcranial magnetic stimulation (TMS). Using either method, the motor cortex can be localized noninvasively, but to date there have been few studies correlating the level of agreement between the two techniques. METHODS: We used fMRI and TMS to localize the motor cortex in a young woman with intractable focal seizures, congenital left arm weakness, and a dysplastic right hemisphere on MRI. RESULTS: There was excellent agreement in the localization of motor representation for each hand. Both were predominantly located in the left hemisphere. fMRI also showed an area of posterior activation in the right hemisphere, but there was no evidence of descending corticospinal projections from this site using TMS, direct cortical stimulation, and Wada testing. CONCLUSIONS: Functional MRI (fMRI) and transcranial magnetic stimulation (TMS) were successfully used to localize cortical motor function before epilepsy surgery. Each technique demonstrated migration of motor function for the left hand to the left motor cortex. After resection of the dysplastic right precentral gyrus there was no permanent increase in weakness or disability. The two techniques are complementary; fMRI indicates all cortical areas activated by the motor task, whereas TMS identifies only those areas giving rise to corticospinal projections.

Presurgical evaluation of the motor hand area with functional MR imaging in patients with tumors and dysplastic lesions.

PURPOSE: To test an optimized functional magnetic resonance (MR) imaging procedure to depict the motor hand representation area (HRA) in patients with epilepsy lesions near the central sulcus. MATERIALS AND METHODS: Fast low-angle shot MR imaging was performed with an oblique single-section imaging technique in eight control subjects (10 hemispheres) and six patients (12 hemispheres). Three series of five activation images (obtained while subjects performed repetitive finger-to-thumb opposition movements) and five rest images were acquired. Each hemisphere was studied in three adjacent sections. Difference maps (obtained with simple subtraction between activation and rest images) were compared with t-test maps. RESULTS: In control subjects, the HRA was visible in 27 of 30 sections. Qualitatively, activation was seen better on t-test maps in 14 and on difference maps in four of these sections. In all patients, motor activation could be seen in the hemisphere that contained the lesion. This activation was considered normal in four patients. In two patients, the HRA was deformed. Functional MR imaging activation in the motor area was confirmed with Penfield stimulation in five patients. CONCLUSION: Functional MR imaging findings in the preoperative assessment of dysplastic lesions around the central sulcus are the same as for tumors. t-test maps are superior to difference maps in the treatment of motor functional MR imaging data.

Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole.

OBJECTIVE: To show that PET with 18F-fluoromisonidazole (18F-FMISO) can detect peri-infarct hypoxic tissue in patients after ischemic stroke. BACKGROUND: PET with (15)O-labeled oxygen and water is the only established method for identifying the ischemic penumbra in humans. We used PET with 18F-FMISO in patients after ischemic stroke to identify hypoxic but viable peri-infarct tissue likely to represent the ischemic penumbra, and to determine how long hypoxic tissues persist after stroke. METHODS: Patients with acute hemispheric ischemic stroke were studied using PET with 18F-FMISO either within 48 hours or 6 to 11 days after stroke onset. The final infarct was defined by CT performed 6 to 11 days after stroke. Tracer uptake was assessed objectively by calculating the mean activity in the contralateral (normal) hemisphere, then identifying pixels with activity greater than 3 SDs above the mean in both hemispheres. Positive studies were those with high-activity pixels ipsilateral to the infarct. RESULTS: Fifteen patients were studied; 13 within 48 hours of stroke, 8 at 6 to 11 days, and 6 during both time periods. Hypoxic tissue was detected in 9 of the 13 patients studied within 48 hours of stroke, generally distributed in the peripheries of the infarct and adjacent peri-infarct tissues. None of the 8 patients studied 6 to 11 days after stroke exhibited increased 18F-FMISO activity. All 6 patients studied both early and late exhibited areas of increased activity during the early but not the late study. CONCLUSIONS: PET with 18F-FMISO can detect peri-infarct hypoxic tissue after acute ischemic stroke. The distribution of hypoxic tissue suggests that it may represent the ischemic penumbra. Hypoxic tissues do not persist to the subacute phase of stroke (6 to 11 days).

Experience with diffusion-weighted imaging in an acute stroke unit.

We performed diffusion-weighted MRI (DWI) on a standard 1.5-tesla MRI scanner using a high-speed stimulated echo pulse sequence (turboSTEAM) in 9 stroke patients and 9 control subjects to investigate whether this technique can be used clinically to assist in ischaemic stroke diagnosis within the time frame for potential therapy. Stroke patients underwent DWI between 3.75 h and 3 days after stroke onset. Three patients were studied on more than one occasion. DWI was normal in the 9 controls. Seven of 9 stroke patients showed areas of increased signal on DWI. DWI detected cerebral ischaemia 3.75 h after stroke onset when both CT and T2-weighted MRI were normal. In 6 DWI-positive patients studied at later times, increased signal on T2-weighted images was present at the same time. Two patients had normal CT, T2-weighted and DWI images; both made good neurological recoveries. For the routine assessment of stroke patients, DWI implemented on a standard MRI system can provide additional information of clinical value to that obtained with conventional pulse sequences. In particular it facilitates early detection of cerebral ischaemia during the first few hours after stroke.

Quantitation of tyrosine hydroxylase and neuropeptide Y immunoreactivity in single rat sympathetic neurons: effects of preganglionic nerve activity.

Using computerised densitometry to measure immunocytochemical reaction product in a model system, we established conditions that produced a linear relationship between the logarithm of antigen concentration and the measured intensity of staining. We then applied the densitometric technique to assess the changes in tyrosine hydroxylase (TH) and neuropeptide tyrosine (NPY) within sympathetic neurons of rat superior cervical ganglion following chronic decentralization and following reserpine treatment. One week after surgical or pharmacological decentralization, there was appreciable reduction of neuronal levels of both TH and NPY. However, there remained considerable variation in the immunoreactivities of individual cells. Three days of treatment with reserpine elevated TH levels but substantially reduced NPY. Both these effects were prevented by prior decentralization of the ganglia. No differences were seen between normotensive and the Otago strain of genetically hypertensive rats, either in basal TH or NPY immunoreactivities or in responses to the maneuvers performed. Comparison of our findings with previous biochemical data indicate that densitometric immunocytochemistry provides an accurate index of neuronally localised antigen concentrations but also allows analysis of interneuronal differences that are not otherwise apparent.