Selective homonuclear polarization transfer for spectroscopic imaging of GABA at 7T.

We develop and implement a selective homonuclear polarization transfer method for the detection of 3.0 ppm C-4 GABA resonance by spectroscopic imaging in the human brain at 7T. This single shot method is demonstrated with simulations and phantoms, which achieves comparable efficiency of detection to that of J-difference editing. The macromolecule resonance that commonly co-edits with GABA is suppressed at 7T through use of a narrow band preacquisition suppression pulse. This technique is implemented in humans with an eight channel transceiver array and high degree B(0) shimming to measure supplementary motor area and thalamic GABA in controls (n = 8) and epilepsy patients (n = 8 total). We find that the GABA/N-acetyl aspartate ratio in the thalamus of control volunteers, well controlled and poorly controlled epilepsy patients are 0.053 ± 0.012 (n = 8), 0.090 ± 0.012 (n = 2), and 0.038 ± 0.009 (n = 6), respectively.

Metabolic networks in epilepsy by MR spectroscopic imaging.

OBJECTIVE: The concept of an epileptic network has long been suggested from both animal and human studies of epilepsy. Based on the common observation that the MR spectroscopic imaging measure of NAA/Cr is sensitive to neuronal function and injury, we use this parameter to assess for the presence of a metabolic network in mesial temporal lobe epilepsy (MTLE) patients. MATERIALS AND METHODS: A multivariate factor analysis is performed with controls and MTLE patients, using NAA/Cr measures from 12 loci: the bilateral hippocampi, thalami, basal ganglia, and insula. The factor analysis determines which and to what extent these loci are metabolically covarying. RESULTS: We extract two independent factors that explain the data's variability in control and MTLE patients. In controls, these factors characterize a 'thalamic' and 'dominant subcortical' function. The MTLE patients also exhibit a 'thalamic' factor, in addition to a second factor involving the ipsilateral insula and bilateral basal ganglia. CONCLUSIONS: These data suggest that MTLE patients demonstrate a metabolic network that involves the thalami, also seen in controls. The MTLE patients also display a second set of metabolically covarying regions that may be a manifestation of the epileptic network that characterizes limbic seizure propagation.

Imaging of Neuromodulation and Surgical Interventions for Epilepsy.

About one-third of epilepsy cases are refractory to medical therapy. During the past decades, the availability of surgical epilepsy interventions has substantially increased as therapeutic options for this group of patients. A wide range of surgical interventions and electrophysiologic neuromodulation techniques are available, including lesional resection, lobar resection, thermoablation, disconnection, multiple subpial transections, vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation. The indications and imaging features of potential complications of the newer surgical interventions may not be widely appreciated, particularly if practitioners are not associated with comprehensive epilepsy centers. In this article, we review a wide range of invasive epilepsy treatment modalities with a particular focus on their postoperative imaging findings and complications. A state-of-the-art treatment algorithm provides context for imaging findings by helping the reader understand how a particular invasive treatment decision is made.

Short echo spectroscopic imaging of the human brain at 7T using transceiver arrays.

Recent advances in magnet technology have enabled the construction of ultrahigh-field magnets (7T and higher) that can accommodate the human head and body. Despite the intrinsic advantages of performing spectroscopic imaging at 7T, increased signal-to-noise ratio (SNR), and spectral resolution, few studies have been reported to date. This limitation is largely due to increased power deposition and B(1) inhomogeneity. To overcome these limitations, we used an 8-channel transceiver array with a short TE (15 ms) spectroscopic imaging sequence. Utilizing phase and amplitude mapping and optimization schemes, the 8-element transceiver array provided both improved efficiency (17% less power for equivalent peak B(1)) and homogeneity (SD(B(1)) = +/-10% versus +/-22%) in comparison to a transverse electromagnetic (TEM) volume coil. To minimize the echo time to measure J-modulating compounds such as glutamate, we developed a short TE sequence utilizing a single-slice selective excitation pulse followed by a broadband semiselective refocusing pulse. Extracerebral lipid resonances were suppressed with an inversion recovery pulse and delay. The short TE sequence enabled visualization of a variety of resonances, including glutamate, in both a control subject and a patient with a Grade II oligodendroglioma.

Visualization of chemokine binding sites on human brain microvessels.

The chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) aid in directing leukocytes to specific locales within the brain and spinal cord during central nervous system inflammation. However, it remains unclear how these chemokines exert their actions across a vascular barrier, raising speculation that interaction with endothelial cells might be required. Therefore, experiments were performed to determine whether binding domains for these chemokines exist along the outer surface of brain microvessels, a feature that could potentially relay chemokine signals from brain to blood. Using a biotinylated chemokine binding assay with confocal microscopy and three-dimensional image reconstruction, spatially resolved binding sites for MCP-1 and MIP-alpha around human brain microvessels were revealed for the first time. Binding of labeled MCP-1 and MIP-1alpha could be inhibited by unlabeled homologous but not heterologous chemokine, and was independent of the presence of heparan sulfate, laminin, or collagen in the subendothelial matrix. This is the first evidence of specific and separate binding domains for MCP-1 and MIP-1alpha on the parenchymal surface of microvessels, and highlights the prospect that specific interactions of chemokines with microvascular elements influence the extent and course of central nervous system inflammation.

Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy.

BACKGROUND: High extracellular glutamate concentrations have been identified as a likely trigger of epileptic seizures in mesial temporal lobe epilepsy (MTLE), but the underlying mechanism remains unclear. We investigated whether a deficiency in glutamine synthetase, a key enzyme in catabolism of extracellular glutamate in the brain, could explain the perturbed glutamate homoeostasis in MTLE. METHODS: The anteromedial temporal lobe is the focus of the seizures in MTLE, and surgical resection of this structure, including the hippocampus, leads to resolution of seizures in many cases. By means of immunohistochemistry, western blotting, and functional enzyme assays, we assessed the distribution, quantity, and activity of glutamine synthetase in the MTLE hippocampus. FINDINGS: In western blots, the expression of glutamine synthetase in the hippocampus was 40% lower in MTLE than in non-MTLE samples (median 44 [IQR 30-58] vs 69 [56-87]% of maximum concentration in standard curve; p=0.043; n=8 and n=6, respectively). The enzyme activity was lower by 38% in MTLE vs non-MTLE (mean 0.0060 [SD 0.0031] vs 0.0097 [0.0042] U/mg protein; p=0.045; n=6 and n=9, respectively). Loss of glutamine synthetase was particularly pronounced in areas of the MTLE hippocampus with astroglial proliferation, even though astrocytes normally have high content of the enzyme. Quantitative immunoblotting showed no significant change in the amount of EAAT2, the predominant glial glutamate transporter in the hippocampus. INTERPRETATION: A deficiency in glutamine synthetase in astrocytes is a possible molecular basis for extracellular glutamate accumulation and seizure generation in MTLE. Further studies are needed to define the cause, but the loss of glutamine synthetase may provide a new focus for therapeutic interventions in MTLE.

Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease.

This report describes the prospective and systematic psychiatric assessment of nine patients who received transplantation of human fetal mesencephalic tissue into the caudate nucleus for treatment of Parkinson's disease. Unlike adrenal medullary transplantation, which often causes psychosis or delirium, this procedure appeared to have few perioperative sequelae. On longer-term follow-up, there was some statistical evidence of deterioration in psychiatric status, as manifested primarily in depressive and nonspecific emotional and behavioral symptoms. This group effect was partly attributable to the occurrence of discrete episodes of illness (major depression and panic disorder with agoraphobia) in some patients, but it was unclear whether such episodes occurred more often than would ordinarily be expected in Parkinson's disease. Differences in the neurobiological effects of fetal mesencephalic and adrenal medullary grafts may account for differences in the psychiatric sequelae of patients receiving these procedures.

Mouse cytomegalovirus in developing brain tissue: analysis of 11 species with GFP-expressing recombinant virus.

Cytomegaloviruses (CMVs) are species-specific large double-stranded DNA viruses. Mouse and human CMVs have a similar morphology, similar gene sequence, and exert similar cellular effects, but the replication of the virus outside its primary host species is limited. This may confer upon CMV certain advantages for expression of foreign genes or cellular labels in brain cells of nonhost species. We examined the ability of recombinant mouse (m)CMV expressing green fluorescent protein (GFP) to serve as a vector for transgene expression in developing neurons and glia outside the normal host species. For comparative purposes, 11 species were examined. Mouse CMV reporter gene expression was particularly strong in the developing brain of its normal host species, mouse, where it replicated in cultures and brain slices, leading to cell death. All mammalian species tested (human, rat, gerbil, hamster, mouse) showed reporter gene expression after mCMV infection. High levels of mCMV infection were also found in chicken central nervous system cells in vitro, and a low level of mCMV expression was found after an initial delay in turtle neurons and glia. No mCMV reporter gene expression was found in frog cells or aplysia neurons or glia or in drosophila or fungal cells. Infection of nonmouse neurons by low concentrations of mCMV led to strong expression of GFP in dendrites and axons with normal morphology. Despite the lack of replication, high doses of mCMV induced morphologic changes in neurons and glia from hamster and rat brain slices, leading to cells rounding up, and to the formation of giant cells consisting of an aggregate of many cells fused together into a syncytium. In contrast, in human hippocampal slices, GFP-expressing cells infected with mCMV had a relatively normal appearance 12 days after inoculation. To determine whether a CMV from another species could serve as a vector for gene transfer, a recombinant human CMV-expressing GFP was used for transgene expression in rat brain cells in vitro. Cytomegaloviruses thus have potential as useful vectors for gene transfer and labeling central nervous system cells, with the actions of CMV being dependent on a number of factors.

The neural substrate of memory impairment demonstrated by the intracarotid amobarbital procedure.

The intracarotid amobarbital sodium (Amytal) procedure (IAP) was performed for 46 patients with temporal lobe epilepsy (21 with left seizure foci; 25 with right seizure foci). After anteromedial temporal lobectomy, neuronal densities were established for hippocampal subfields CA1, CA2, and CA3; the hilum; and the dentate granule cell layer. Intracarotid amobarbital procedure memory results were related to CA3 neuronal loss only. Patients who did not demonstrate memory after injection contralateral to the seizure focus had significantly fewer cells in CA3 than patients who did. Additionally, a significant correlation was observed between the intracarotid amobarbital procedure memory examination raw score after injection contralateral to the seizure focus and CA3 cell density. Using chi 2 analysis, significant differences were documented in the frequency with which memory was demonstrated after injection contralateral to the seizure focus for groups of patients classified by degree of CA3 neuronal loss. This finding supports prior research showing subfield specificity in some memory processes.

A cerebral effect of carotid sinus stimulation. Observation during intraoperative electroencephalographic monitoring.

Surgical manipulation in the region of the carotid sinus resulted in diffuse electroencephalographic slowing in two patients, despite the absence of bradycardia or hypotension. Direct observation confirmed the absence of carotid compression. The effect was abolished by infiltration of lidocaine hydrochloride into the carotid sinus area. Carotid clamping in one patient failed to produce similar electroencephalographic changes. We believe that this is the first observation of an influence of carotid sinus stimulation on human cerebral activity not attributable to reflex cardiovascular changes or complicated by the possibility of carotid compression.

Diagnosis of medial temporal lobe seizure onset: relative specificity and sensitivity of quantitative MRI.

Measurement of hippocampal volume by MRI is a new technique with potential value in the localization of epileptic regions, but whether reduced hippocampal volume predicts the location of electrical seizure onset in mixed patient groups is not known. We examined the sensitivity and specificity of this technique among 56 refractory epileptic patients for the diagnosis of medial temporal lobe epilepsy as judged by intracranial EEG recording of spontaneous seizure onset. Since these patients had intracranial EEG because of inconsistent or insufficient localization by noninvasive electrophysiologic, functional, and structural assessment, this patient population can be considered the most difficult to localize. Hippocampal atrophy by MRI volumetry was 75% sensitive to, and 64% specific for, ipsilateral medial temporal lobe seizure onset in this group. Hippocampal atrophy was significantly correlated with longer duration of epilepsy. MRI compared favorably with all other noninvasive means of localization, which had 41 to 73% sensitivity and 45 to 65% specificity to medial temporal ictal onset; of these, none had as acceptable a combination of both adequate sensitivity and specificity. We conclude that MRI volumetry of the hippocampus is a valuable, noninvasive localization method in chronic epilepsy, with a yield and accuracy surpassing all other noninvasive studies used to predict the presence of medial temporal seizure onset.

Seizure localization and pathology following head injury in patients with uncontrolled epilepsy.

We studied seizure localization and surgical pathology in 25 patients who developed intractable complex partial seizures following head trauma. All patients underwent an extensive presurgical evaluation that included MRI, neuropsychological evaluation, and surface EEG monitoring, and 21 had intracranial EEG monitoring. Seizures were successfully localized in nine patients; all nine underwent a surgical procedure and are seizure-free. Six of these patients had a mesial temporal lobe seizure focus, of whom five had a pathologic diagnosis of mesial temporal sclerosis. All five patients who developed mesial temporal sclerosis sustained their head injury at or before age 5 years. The three remaining patients whose seizures were successfully localized had neocortical foci and circumscribed radiographic abnormalities, which were presumed to be secondary to head trauma, and all had successful surgical resections of the epileptogenic focus. The remaining 16 patients sustained later trauma, and all had successful surgical resections of the epileptogenic focus. The remaining 16 patients sustained later trauma and did not have a focal MRI lesion, and their seizures were not adequately localized. We conclude that as a group, seizure foci secondary to head trauma are difficult to localize accurately, and this should deter surgical intervention. There was an association between early head injury (ie, at or before age 5 years) and mesial temporal sclerosis, and this association aided seizure localization and successful surgical intervention. Therefore, under the right circumstances, trauma can be a suitable historical element in the profile of patients in whom epilepsy surgery is successful.

Characteristics of intractable seizures following meningitis and encephalitis.

We studied clinical seizure characteristics, seizure localization, and pathology in 38 patients who developed medically intractable partial seizures following meningitis (n = 16) or encephalitis (n = 22) and were evaluated for epilepsy surgery. Whereas meningitis in this group was commonly associated with mesial temporal sclerosis (MTS), most encephalitis patients had neocortical foci. The age of onset of the encephalitic illness was important in predicting mesial temporal or neocortical foci in that group: encephalitis before, but not after, age 4 years was associated with MTS. Since almost all meningitis occurred before age 4 years, these data support the hypothesis that the medial temporal lobe is particularly susceptible to early insults, establishing the initial pathologic entity of MTS and the subsequent cascade of partial seizures. Later-onset encephalitis produced extrahippocampal neocortical seizure foci, was rarely associated with MRI abnormality, and was difficult to localize precisely. In contrast, meningitis was commonly associated with MTS, aiding seizure localization and successful surgical intervention when seizures were medically uncontrolled.

EEG findings in frontal lobe epilepsies.

As a group, epilepsies of frontal lobe origin are thought to be poorly localized using surface EEG recordings. This finding may depend on the specific areas of frontal lobe from which the seizures originate or the pathologic substrate. We reviewed the presurgical surface EEGs of patients with frontal lobe epilepsy who underwent epilepsy surgery. The specific area of the frontal lobe where seizures originated was determined by 1) intracranial ictal EEG recordings, or 2) the presence of a structural lesion, identified by imaging studies in patients who achieved complete seizure control following surgery. We differentiated patients whose seizures began in the dorsolateral frontal convexity from those whose seizures began in the medial frontal region, and we correlated EEG findings in the interictal, postictal, and ictal states with seizure semiology, pathologic substrate, and surgical outcome. Four of nine patients had seizures originating in the dorsolateral frontal convexity and five had medial frontal onset seizures. Patients whose seizures originated from the dorsolateral convexity had focal interictal epileptiform abnormalities that localized to the region of seizure onset. Patients whose seizures began in the medial frontal region had either no interictal epileptiform abnormality or had multifocal epileptiform discharges. Patients whose seizures began in the dorsolateral convexity showed focal electrographic seizure activity that was localizing. This rhythmic fast activity did not appear to be substrate-specific. Patients whose seizure onset localized to the medial frontal region did not show focal electrographic seizure at clinical onset. We conclude that the scalp EEG recordings of frontal lobe epilepsies contain features that enable differentiation of seizures originating from two different regions of the frontal lobe.

Combined depth and subdural electrode investigation in uncontrolled epilepsy.

We used both depth and subdural electrodes to obtain localization of the seizure focus in 47 medically refractory epileptic patients. Seizures were localized in 33 patients. Onset was consistently localized by the depth electrodes in 23 patients, was variable or simultaneous in depth and subdural electrodes in 6 (in the same lobe), and was consistently localized to subdural electrodes in 4. All patients localized with subdural electrodes were extratemporal and 3 of the 4 had lesions on imaging studies which helped guide location of electrode placement. Eighty-seven percent of temporal lobe seizures began in hippocampus (recorded by the depth electrode), and 80% were eventually propagated to the ipsilateral temporal neocortex (recorded by the subdural electrode). In 8 patients with bilateral temporal depth and subdural recording, seizures never spread to the contralateral neocortex before the ipsilateral neocortex. Subdural electrodes were 20% less sensitive than depth electrodes in detection of seizures beginning in hippocampus but were accurate when lateralized. Variable or simultaneous unilateral neocortical versus hippocampal temporal lobe seizure onset, determined by the combined study, was significantly correlated with less favorable seizure control after anteromedial temporal lobectomy and hippocampectomy.

Surface and depth EEG findings in patients with hippocampal atrophy.

OBJECTIVE: To establish if MRI evidence of hippocampal atrophy (HcA) is an independent surrogate of EEG criteria for the diagnosis of medial temporal lobe (MTL) epilepsy (MTLE). BACKGROUND: MRI evidence of HcA has been shown to correlate with mesial temporal sclerosis (MTS), intracranial evidence of MTL seizure onset, and outcome after temporal lobectomy. The reported rate of discordance between scalp ictal EEG recordings and MRI evidence of unilateral HcA ranges from rare to moderate. We examined the surface and depth ictal EEG findings of patients with HcA, as detected by volumetric MRI, to clarify their significance in detecting areas of epileptogenicity in this group of patients. METHODS: From a group of patients with refractory epilepsy, we identified 119 patients with HcA (97 with unilateral and 13 with bilateral HcA, 9 with HcA and mass lesion). MRI volumetric studies were used to obtain Hc ratios. Absolute volumes were used to detect bilateral atrophy. Surface and depth EEG recordings were analyzed for localization of ictal abnormalities, and their distribution was compared for concordance with the location of HcA. Surgical outcome was reviewed. RESULTS: Of the 110 patients with isolated HcA, 63 had surgery; 82% of ictal depth EEG onsets were concordant with the atrophic Hc, and 72% ictal surface EEG onsets were concordant. Four patients with concordant EEG and HcA failed to achieve seizure control with resection of the atrophic Hc. Furthermore, 3 patients with discordant EEG and HcA had resection of the non-atrophic Hc with excellent results. Among the 47 non-operated patients, 54% had discordant or unlocalized ictal depth EEG results and 52% had discordant ictal surface EEG. Four of the 9 lesional patients with HcA had excellent outcome after lesionectomy without hippocampectomy. CONCLUSION: The presence of HcA is not an independent predictor of the site of epileptogenesis.

Measurement of carbamazepine and carbamazepine epoxide in the human brain using in vivo microdialysis.

We report the first study of carbamazepine and carbamazepine-10,11-epoxide concentrations determined by using intracerebral microdialysis in three patients undergoing depth electrode studies for the evaluation of medically intractable epilepsy. Very small microdialysis catheters, affixed to and inserted with the depth electrodes, sampled drug concentration in the extracellular environment. We perfused artificial extracellular fluid continuously, and varied the perfusion rate to permit estimation of the absolute drug concentration in the extracellular space. Serum samples were obtained simultaneously. The relation between dialysate and extracellular concentration (recovery fraction) depended, in vivo but not in vitro, on the relative lipophilicity of the compounds, suggesting that diffusion of the drug within the brain is a major determinant of microdialysate drug concentration. When this is taken into account, the steady-state extracellular concentrations of these compounds closely mirror their unbound serum concentrations.

Verbal memory impairment resulting from hippocampal neuron loss among epileptic patients with structural lesions.

We recently demonstrated statistically significant correlations between presurgical memory impairment and hippocampal volumetric cell densities (in CA3 and the hilar area only) for patients with idiopathic left temporal lobe epilepsy who exhibited marked hippocampal neuron loss. In the present research we determine whether the same relationship exists for patients with structural lesions, in whom hippocampal neuron loss was minimal. Rank-order correlations of verbal memory test results (ie, Long Term Retrieval score of the verbal Selective Reminding Test, Percent Retention index of the Logical Memory subtest of the Wechsler Memory Scale) and hippocampal volumetric cell densities (subfields CA1, CA2, CA3, the hilar area, and the granule layer of area dentata) were computed for 22 patients with structural lesions and medically refractory epilepsy of temporal lobe onset (11 left, 11 right). There were statistically significant correlations between Long Term Retrieval and the volumetric cell density of CA1 (r = 0.62, p < 0.05) and between percent retention and the volumetric cell density of CA2 (r = 0.60, p < 0.05) for patients with left hemisphere lesions. No other correlations were found for patients with left or right temporal lobe lesions.

Sexual automatisms in complex partial seizures.

Ictal sexual automatisms such as masturbatory activity, pelvic thrusting, or similar automatisms for which the patient is amnesic have been attributed to temporal lobe disease. Of 61 patients with medically refractory complex partial seizures, 14 had frontal lobe seizure foci. Four of these patients manifested sexual automatisms in some or all of their seizures. Frontal lobe seizure origin was documented by depth EEG in three patients. In the fourth, a calcified lesion was demonstrated radiologically. In three patients, frontal lobectomy revealed abnormal frontal lobe pathology and was followed by 75 to 100% reduction in seizure frequency. Sexual automatisms did not occur in patients with seizures originating in any area other than the frontal lobe.

Intracerebral masses in patients with intractable partial epilepsy.

One hundred ninety patients were considered for surgical treatment of uncontrolled partial seizures. Twenty-seven (15%) had intracranial mass lesions detected during preoperative evaluation. Seizures were present for a mean of 10 years. Sixty percent of the patients had prior negative radiologic studies. The lesions included 19 neoplasms and 8 non-neoplastic structural (non-atrophic) lesions. Refractory simple partial seizures and a changing neurologic examination were more commonly associated with neoplasms. Treatment included biopsy and radiation, mass resection, or subtotal lobectomy. Although any form of treatment gave better seizure control, patients undergoing subtotal lobectomy had more than 95% reduction in seizures.