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1.  Association of Human Herpesvirus-6B with Mesial Temporal Lobe Epilepsy 
PLoS Medicine  2007;4(5):e180.
Background
Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)–positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.
Methods and Findings
HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive—the first demonstration of an ex vivo HHV-6–infected astrocyte culture isolated from HHV-6–positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.
Conclusions
Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.
Steve Jacobson and colleagues report finding human herpesvirus-6B DNA in brain resections from 11 of 16 patients with mesial temporal lobe epilepsy, strengthening the evidence for a role for this virus in this condition.
Editors' Summary
Background.
Epilepsy is a common brain disorder caused by a sudden, excessive electrical discharge in a cluster of neurons—the cells that transmit electrical messages between the body and the brain. Its symptoms depend on which part of the brain is affected by this electrical firestorm and how far the disturbance spreads. When only part of the brain is affected (a partial seizure or fit), patients may see or smell strange things, recall forgotten memories, or have part of their body jerk uncontrollably. When the electrical disturbance spreads across the whole brain (a generalized seizure), there may be loss of consciousness and/or the whole body may become rigid or jerk. Epilepsy is usually controlled with anti-epileptic drugs or, in very severe focal cases, surgery to the area of the brain where the seizure starts. Although head injuries or brain tumors can trigger epilepsy, the cause of most cases of epilepsy is unknown.
Why Was This Study Done?
Knowing what causes epilepsy might lead to better treatments for it. One possibility is that infections trigger epilepsy. The researchers in this study asked whether infections with human herpesvirus 6B (HHV-6B) are associated with a common type of epilepsy called mesial temporal lobe epilepsy (MTLE). Patients with MTLE often have extensive scarring in the hippocampus, a brain region responsible for memory that lies deep within a bigger region called the temporal lobe. Hippocampal scarring and MTLE are associated with a history of fever-induced fits, and HHV-6B infection can cause such fits in young children. Most people become infected with HHV-6B (or the closely related HHV-6A) early in life. The virus then remains latent for years within the brain and elsewhere. Given these facts and a previous investigation that showed that brain tissue from several patients with MTLE contained HHV-6B, the researchers reasoned that it was worth investigating HHV-6B as a cause of MTLE.
What Did the Researchers Do and Find?
The researchers first looked for HHV-6B DNA in brain tissue surgically removed from patients with MTLE or another type of epilepsy. Tissue from 11 of 16 patients with MTLE (but from 0 of 7 control patients) contained HHV-6B DNA. When the researchers grew astrocytes (a type of brain cell) from some of these samples, only those from HHV-6B DNA-positive samples from patients with MTLE expressed an HHV-6-specific protein. Next, the researchers investigated in detail a patient with MTLE who had four sequential operations to control his epilepsy. This patient's hippocampus, which was removed in his first operation, contained a higher level of HHV-6B DNA than the tissues removed in later operations. After the fourth operation (which removed half of his brain and cured his epilepsy), astrocytes grown from the temporal lobe and the frontal/parietal lobe (a brain region next to the temporal lobe) but not the frontal and occipital lobes contained HHV-6B DNA and expressed a viral protein. The researchers also measured the production by these various astrocytes of a substance that moves glutamate (an amino acid that also acts as a neurotransmitter) across cell membranes—MTLE has been associated with a glutamate transporter deficiency. Consistent with this, astrocytes from the patient's temporal lobe made no glutamate transporter mRNA (mRNA is an essential precursor for protein to be produced). Finally, infection of astrocytes isolated from a patient without MTLE with HHV-6B greatly reduced expression of glutamate transporter in these astrocytes.
What Do These Findings Mean?
These findings, together with those from the previous study, reveal that nearly two-thirds of patients with MTLE (but no patients with other forms of epilepsy) have an active HHV-6B infection in the brain region where their epilepsy originates. Overall, they provide strong support for the idea that HHV-6B infections might cause MTLE, particularly given the results obtained from the patient whose condition only improved after multiple brain operations had removed all the virally infected material. Furthermore, the demonstration that HHV-6B infection reduces glutamate transporter expression in astrocytes suggests that HHV-6B infection might cause astrocyte dysfunction. This dysfunction could lead to injury of the sensitive neurons in the hippocampus and trigger MTLE. Additional patients now need to be studied both to confirm the association between HHV-6B infection and MTLE and to discover exactly how this virus triggers epilepsy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040180.
MedlinePlus encyclopedia page on epilepsy (in English and Spanish)
World Health Organization fact sheet on epilepsy (in English, French, Spanish, Russian, Arabic, and Chinese)
US National Institute for Neurological Disorders and Stroke epilepsy information page (in English and Spanish)
UK National Health Service Direct information for patients on epilepsy (in several languages)
Neuroscience for kids, an educational Web site prepared by Eric Chudler (University of Washington, Seattle, Washington, United States), who also has a site that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
A short scientific article on human herpes virus 6 in the journal Emerging Infectious Diseases
doi:10.1371/journal.pmed.0040180
PMCID: PMC1880851  PMID: 17535102
2.  Epilepsy (partial) 
Clinical Evidence  2011;2011:1214.
Introduction
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of starting antiepileptic drug treatment following a single seizure? What are the effects of drug monotherapy in people with partial epilepsy? What are the effects of additional drug treatments in people with drug-resistant partial epilepsy? What is the risk of relapse in people in remission when withdrawing antiepileptic drugs? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiepileptic drugs after a single seizure; monotherapy for partial epilepsy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs for drug-resistant partial epilepsy (allopurinol, eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, retigabine, tiagabine, topiramate, vigabatrin, or zonisamide); antiepileptic drug withdrawal for people with partial or generalised epilepsy who are in remission; behavioural and psychological treatments for partial or generalised epilepsy (biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, relaxation therapy (alone or plus behavioural modification therapy, yoga); and surgery for drug-resistant temporal lobe epilepsy ( lesionectomy, temporal lobectomy, vagus nerve stimulation as adjunctive therapy).
Key Points
During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission.
After a first seizure, antiepileptic drugs may delay or prevent subsequent seizures, but they can cause adverse effects, and their long-term benefit is unknown. Antiepileptic drug treatment after a single seizure does not reduce the risk of drug refractory epilepsy in the long term.
Carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, and topiramate are widely considered effective in controlling seizures in newly diagnosed partial epilepsy, but we found no RCTs comparing them with placebo, and a placebo-controlled trial would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs. Adding second-line drugs to usual treatment reduces seizure frequency in people with drug-resistant partial epilepsy, but it increases adverse effects such as dizziness and somnolence. We don't know if any one antiepileptic drug is more likely to reduce seizures compared with the others.
CAUTION: Vigabatrin, which may be used as second-line treatment, causes concentric visual-field abnormalities in about 40% of people, which are probably irreversible.
In people who have been seizure free for at least 2 years on treatment, almost 60% of those with partial or generalised epilepsy who withdraw from antiepileptic treatment will remain seizure free, compared with almost 80% of people who continue treatment.
Educational programmes may reduce seizure frequency and improve psychosocial functioning in people with partial or generalised epilepsy, but we don't know whether relaxation, yoga, biofeedback, CBT, relaxation plus behavioural modification, or family counselling are beneficial.
There is consensus that temporal lobectomy or amygdalohippocampectomy can improve seizure control and quality of life in people with drug-resistant temporal lobe epilepsy, but they can cause neurological adverse effects.
High-level vagus nerve stimulation may reduce seizure frequency in people with drug-resistant partial seizures, but it may cause hoarseness and dyspnoea, and long-term effects are unknown. We don't know whether different stimulation cycles are more effective at reducing seizure frequency or at increasing the proportion of responders.
We don't know whether lesionectomy improves seizure control in people with drug-resistant temporal lobe epilepsy.
PMCID: PMC3217777  PMID: 21549021
3.  Impaired and facilitated functional networks in temporal lobe epilepsy☆ 
NeuroImage : Clinical  2013;2:862-872.
How epilepsy affects brain functional networks remains poorly understood. Here we investigated resting state functional connectivity of the temporal region in temporal lobe epilepsy. Thirty-two patients with unilateral temporal lobe epilepsy underwent resting state blood-oxygenation level dependent functional magnetic resonance imaging. We defined regions of interest a priori focusing on structures involved, either structurally or metabolically, in temporal lobe epilepsy. These structures were identified in each patient based on their individual anatomy. Our principal findings are decreased local and inter-hemispheric functional connectivity and increased intra-hemispheric functional connectivity ipsilateral to the seizure focus compared to normal controls. Specifically, several regions in the affected temporal lobe showed increased functional coupling with the ipsilateral insula and immediately neighboring subcortical regions. Additionally there was significantly decreased functional connectivity between regions in the affected temporal lobe and their contralateral homologous counterparts. Intriguingly, decreased local and inter-hemispheric connectivity was not limited or even maximal for the hippocampus or medial temporal region, which is the typical seizure onset region. Rather it also involved several regions in temporal neo-cortex, while also retaining specificity, with neighboring regions such as the amygdala remaining unaffected. These findings support a view of temporal lobe epilepsy as a disease of a complex functional network, with alterations that extend well beyond the seizure onset area, and the specificity of the observed connectivity changes suggests the possibility of a functional imaging biomarker for temporal lobe epilepsy.
Highlights
•We studied functional connectivity changes in patients with temporal lobe epilepsy.•Patients had decreased local and inter-hemispheric functional connectivity.•Patients had increased intra-hemispheric connectivity, ipsilateral to seizure focus.•Functional changes involved several neocortical sites, including the insula.•This pattern may have usefulness as a non-invasive method for presurgical planning.
doi:10.1016/j.nicl.2013.06.011
PMCID: PMC3777845  PMID: 24073391
Epilepsy; Temporal lobe; Hippocampus; Insula; fMRI; Functional connectivity
4.  Impaired and Facilitated Functional Networks in Temporal Lobe Epilepsy 
NeuroImage : clinical  2013;2:862-872.
How epilepsy affects brain functional networks remains poorly understood. Here we investigated resting state functional connectivity of the temporal region in temporal lobe epilepsy. Thirty-two patients with unilateral temporal lobe epilepsy underwent resting state blood-oxygenation level dependent functional magnetic resonance imaging. We defined regions of interest a priori focusing on structures involved, either structurally or metabolically, in temporal lobe epilepsy. These structures were identified in each patient based on their individual anatomy. Our principal findings are decreased local and inter-hemispheric functional connectivity and increased intra-hemispheric functional connectivity ipsilateral to the seizure focus compared to normal controls. Specifically, several regions in the affected temporal lobe showed increased functional coupling with the ipsilateral insula and immediately neighboring subcortical regions. Additionally there was significantly decreased functional connectivity between regions in the affected temporal lobe and their contralateral homologous counterparts. Intriguingly, decreased local and inter-hemispheric connectivity was not limited or even maximal for the hippocampus or medial temporal region, which is the typical seizure onset region. Rather it also involved several regions in temporal neo-cortex, while also retaining specificity, with neighboring regions such as the amygdala remaining unaffected. These findings support a view of temporal lobe epilepsy as a disease of a complex functional network, with alterations that extend well beyond the seizure onset area, and the specificity of the observed connectivity changes suggests the possibility of a functional imaging biomarker for temporal lobe epilepsy.
doi:10.1016/j.nicl.2013.06.011
PMCID: PMC3777845  PMID: 24073391
epilepsy; temporal lobe; hippocampus; insula; fMRI; functional connectivity
5.  A functional magnetic resonance imaging study mapping the episodic memory encoding network in temporal lobe epilepsy 
Brain  2013;136(6):1868-1888.
Functional magnetic resonance imaging has demonstrated reorganization of memory encoding networks within the temporal lobe in temporal lobe epilepsy, but little is known of the extra-temporal networks in these patients. We investigated the temporal and extra-temporal reorganization of memory encoding networks in refractory temporal lobe epilepsy and the neural correlates of successful subsequent memory formation. We studied 44 patients with unilateral temporal lobe epilepsy and hippocampal sclerosis (24 left) and 26 healthy control subjects. All participants performed a functional magnetic resonance imaging memory encoding paradigm of faces and words with subsequent out-of-scanner recognition assessments. A blocked analysis was used to investigate activations during encoding and neural correlates of subsequent memory were investigated using an event-related analysis. Event-related activations were then correlated with out-of-scanner verbal and visual memory scores. During word encoding, control subjects activated the left prefrontal cortex and left hippocampus whereas patients with left hippocampal sclerosis showed significant additional right temporal and extra-temporal activations. Control subjects displayed subsequent verbal memory effects within left parahippocampal gyrus, left orbitofrontal cortex and fusiform gyrus whereas patients with left hippocampal sclerosis activated only right posterior hippocampus, parahippocampus and fusiform gyrus. Correlational analysis showed that patients with left hippocampal sclerosis with better verbal memory additionally activated left orbitofrontal cortex, anterior cingulate cortex and left posterior hippocampus. During face encoding, control subjects showed right lateralized prefrontal cortex and bilateral hippocampal activations. Patients with right hippocampal sclerosis showed increased temporal activations within the superior temporal gyri bilaterally and no increased extra-temporal areas of activation compared with control subjects. Control subjects showed subsequent visual memory effects within right amygdala, hippocampus, fusiform gyrus and orbitofrontal cortex. Patients with right hippocampal sclerosis showed subsequent visual memory effects within right posterior hippocampus, parahippocampal and fusiform gyri, and predominantly left hemisphere extra-temporal activations within the insula and orbitofrontal cortex. Correlational analysis showed that patients with right hippocampal sclerosis with better visual memory activated the amygdala bilaterally, right anterior parahippocampal gyrus and left insula. Right sided extra-temporal areas of reorganization observed in patients with left hippocampal sclerosis during word encoding and bilateral lateral temporal reorganization in patients with right hippocampal sclerosis during face encoding were not associated with subsequent memory formation. Reorganization within the medial temporal lobe, however, is an efficient process. The orbitofrontal cortex is critical to subsequent memory formation in control subjects and patients. Activations within anterior cingulum and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment.
doi:10.1093/brain/awt099
PMCID: PMC3673458  PMID: 23674488
temporal lobe epilepsy; episodic memory; functional MRI
6.  Amygdala volumetry in "imaging-negative" temporal lobe epilepsy 
Objective: Although amygdala abnormalities are sometimes suspected in "imaging-negative" patients with video EEG confirmed unilateral focal epilepsy suggestive of temporal lobe epilepsy (TLE), amygdala asymmetry is difficult to assess visually. This study examined a group of "imaging-negative" TLE patients, estimating amygdala volumes, to determine whether cryptic amygdala lesions might be detected.
Methods: Review of video EEG monitoring data yielded 11 patients with EEG lateralised TLE and normal structural imaging. Amygdala volumes were estimated in this group, in 77 patients with pathologically verified hippocampal sclerosis (HS), and in 77 controls.
Results: Seven of 11 "imaging-negative" cases had both significant amygdala asymmetry and amygdala enlargement, concordant with seizure lateralisation. Although significant amygdala asymmetry occurred in 35 of 77 HS patients, it was never attributable to an abnormally large ipsilateral amygdala. Compared with patients with HS, patients with amygdala enlargement were less likely to have suffered secondarily generalised seizures (p<0.05), and had an older age of seizure onset (p<0.01).
Conclusion: Abnormal amygdala enlargement is reported in seven cases of "imaging-negative" TLE. Such abnormalities are not observed in patients with HS. It is postulated that amygdala enlargement may be attributable to a developmental abnormality or low grade tumour. It is suggested that amygdala volumetry is indicated in the investigation and diagnosis of "imaging-negative" TLE.
doi:10.1136/jnnp.74.9.1245
PMCID: PMC1738652  PMID: 12933928
7.  Voxel based morphometry of grey matter abnormalities in patients with medically intractable temporal lobe epilepsy: effects of side of seizure onset and epilepsy duration 
Objectives: To investigate the use of whole brain voxel based morphometry (VBM) and stereological analysis to study brain morphology in patients with medically intractable temporal lobe epilepsy; and to determine the relation between side, duration, and age of onset of temporal lobe epilepsy, history of childhood febrile convulsions, and grey matter structure.
Methods: Three dimensional magnetic resonance images were obtained from 58 patients with left sided seizure onset (LSSO) and 58 patients with right sided seizure onset (RSSO), defined using EEG and foramen ovale recordings in the course of presurgical evaluation for temporal lobectomy. Fifty eight normal controls formed a comparison group. VBM was used to characterise whole brain grey matter concentration, while the Cavalieri method of modern design stereology in conjunction with point counting was used to estimate hippocampal and amygdala volume. Age and sex were used as confounding covariates in analyses.
Results: LSSO and RSSO patients showed significant reductions in volume (using stereology) and grey matter concentration (using VBM) of the hippocampus, but not of the amygdala, in the presumed epileptogenic zone when compared with controls, but hippocampal (and amygdala) volume and grey matter concentration were not related to duration or age of onset of epilepsy. LSSO and RSSO patients with a history of childhood febrile convulsions had reduced hippocampal volumes in the presumed epileptogenic zone compared with patients without such a history. Left amygdala volume was also reduced in LSSO patients with a history of childhood convulsions. VBM results indicated bilateral thalamic, prefrontal, and cerebellar GMC reduction in patients, which correlated with duration and age of onset of epilepsy.
Conclusions: Hippocampal sclerosis is not necessarily the consequence of recurrent temporal lobe seizures. A major cause of hippocampal sclerosis appears to be an early aberrant neurological insult, such as childhood febrile seizures. Secondary brain abnormalities exist in regions outside the presumed epileptogenic zone and may result from recurrent seizures.
doi:10.1136/jnnp.73.6.648
PMCID: PMC1757338  PMID: 12438464
8.  Pathology and Pathophysiology of the Amygdala in Epileptogenesis and Epilepsy 
Epilepsy research  2008;78(2-3):102-116.
Acute brain insults, such as traumatic brain injury, status epilepticus, or stroke are common etiologies for the development of epilepsy, including temporal lobe epilepsy (TLE), which is often refractory to drug therapy. The mechanisms by which a brain injury can lead to epilepsy are poorly understood. It is well recognized that excessive glutamatergic activity plays a major role in the initial pathological and pathophysiological damage. This initial damage is followed by a latent period, during which there is no seizure activity, yet a number of pathophysiological and structural alterations are taking place in key brain regions, that culminate in the expression of epilepsy. The process by which affected/injured neurons that have survived the acute insult, along with well-preserved neurons are progressively forming hyperexcitable, epileptic neuronal networks has been termed epileptogenesis. Understanding the mechanisms of epileptogenesis is crucial for the development of therapeutic interventions that will prevent the manifestation of epilepsy after a brain injury, or reduce its severity. The amygdala, a temporal lobe structure that is most well known for its central role in emotional behavior, also plays a key role in epileptogenesis and epilepsy. In this article, we review the current knowledge on the pathology of the amygdala associated with epileptogenesis and/or epilepsy in TLE patients, and in animal models of TLE. In addition, because a derangement in the balance between glutamatergic and GABAergic synaptic transmission is a salient feature of hyperexcitable, epileptic neuronal circuits, we also review the information available on the role of the glutamatergic and GABAergic systems in epileptogenesis and epilepsy in the amygdala.
doi:10.1016/j.eplepsyres.2007.11.011
PMCID: PMC2272535  PMID: 18226499
9.  Increased In Vivo Expression of an Inflammatory Marker in Temporal Lobe Epilepsy 
Animal studies and clinical observations suggest that epilepsy is associated with inflammation. Translocator protein (TSPO) (18 kDa), a marker of inflammation, is increased in vitro in surgical samples from patients with temporal lobe epilepsy. TSPO can be measured in the living human brain with PET and the novel radioligand 11C-PBR28. In this study, we sought to determine whether in vivo expression of TSPO is increased ipsilateral to the seizure focus in patients with temporal lobe epilepsy.
Methods
Sixteen patients with unilateral temporal lobe epilepsy and 30 healthy subjects were studied with 11C-PBR28 PET and MRI. Uptake of radioactivity after injection of 11C-PBR28 was measured from regions of interest drawn bilaterally onto MR images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired-samples t test.
Results
We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without.
Conclusion
We found increased uptake of radioactivity after injection of 11C-PBR28 ipsilateral to the seizure focus in patients with temporal lobe epilepsy, suggesting increased expression of TSPO. Studies in larger samples are required to confirm this finding and determine the clinical utility of imaging TSPO in temporal lobe epilepsy.
doi:10.2967/jnumed.111.091694
PMCID: PMC3832892  PMID: 22238156
positron emission tomography; translocator protein 18 kDa; epilepsy; inflammation
10.  Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus 
Neuroscience  2011;178:208-217.
The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus.
Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala.
doi:10.1016/j.neuroscience.2011.01.029
PMCID: PMC3048957  PMID: 21256929
human; pain; amygdala; hippocampus; causality; fear conditioning
11.  Perfusion patterns in postictal 99mTc-HMPAO SPECT after coregistration with MRI in patients with mesial temporal lobe epilepsy 
OBJECTIVES—To assess patterns of postictal cerebral blood flow in the mesial temporal lobe by coregistration of postictal 99mTc-HMPAO SPECT with MRI in patients with confirmed mesial temporal lobe epilepsy.
METHODS—Ten postictal and interictal 99mTc-HMPAO SPECT scans were coregistered with MRI in 10 patients with confirmed mesial temporal lobe epilepsy. Volumetric tracings of the hippocampus and amygdala from the MRI were superimposed on the postictal and interictal SPECT. Asymmetries in hippocampal and amygdala SPECT signal were then calculated using the equation:
 % Asymmetry =100 × (right − left) / (right + left)/2.
RESULTS—In the postictal studies, quantitative measurements of amygdala SPECT intensities were greatest on the side of seizure onset in all cases, with an average % asymmetry of 11.1, range 5.2-21.9.Hippocampal intensities were greatest on the side of seizure onset in six studies, with an average % asymmetry of 9.6, range 4.7-12.0.In four scans the hippocampal intensities were less on the side of seizure onset, with an average % asymmetry of 10.2, range 5.7-15.5.There was no localising quantitative pattern in interictal studies.
CONCLUSIONS—Postictal SPECT shows distinctive perfusion patterns when coregistered with MRI, which assist in lateralisation of temporal lobe seizures. Hyperperfusion in the region of the amygdala is more consistently lateralising than hyperperfusion in the region of the hippocampus in postictal studies.


PMCID: PMC2169655  PMID: 9285464
12.  Temporal lobe epilepsy with amygdala enlargement: a subtype of temporal lobe epilepsy 
BMC Neurology  2014;14(1):194.
Background
Some recent studies suggest that some imaging-negative temporal lobe epilepsy (TLE) had significant amygdala enlargement (AE). Contradictory data were also reported in previous studies regarding the association between AE and TLE. The present study was to investigate the clinical characters of a group of TLE with AE and compare the amygdala volume of the same patient before and after antiepileptic drugs treatment by a larger sample size.
Methods
This study recruited 33 mesial TLE patients with AE and 35 healthy volunteers. The clinical history, seizure semiology, electroencephalogram (EEG), fluorodeoxyglucose-positron emission tomography (FDG-PET) and amygdala volume were investigated. The amygdala volume were compared between ipsilateral and contralateral sides, TLE patients and 35 healthy controls, and patients at first and follow-up visit by 3.0 T MRI.
Results
Average seizure onset age was 42.0 years (SD 14.3). All patients had complex partial seizures, fourteen had occasional generalized tonic-clonic seizures which often happened during sleep. Ninety percent patients suffered from anxiety or depression. Thirty percent patients had memory decline. Interictal epileptiform discharges appeared predominantly in the anterior or inferior temporal area ipsilateral to AE. Interictal FDG-PET showed regional glucose hypometabolism in the ipsilateral temporal lobe. No hippocampal sclerosis (HS) was suspected in all patients. 22 patients demonstrated good seizure control and significantly reduced volume of the enlarged amygdala after treatment (P < 0.01). The other 11 patients showed initial response to treatment, followed by a gradual increase in seizure frequency over time, and no volume change of the enlarged amygdala after treatment.
Conclusions
TLE with AE probably represents a distinct nosological and probably less homogeneous syndrome which is most likely a subtype of TLE without ipsilateral HS. The chronic and long lasting inflammatory processes or focal cortical dysplasia could lead to amygdala enlargement possibly.
doi:10.1186/s12883-014-0194-z
PMCID: PMC4210593  PMID: 25269594
Amygdala enlargement; Amygdala volume; Temporal lobe epilepsy
13.  Voxel-based T2 Relaxation Rate Measurements in Temporal Lobe Epilepsy (TLE) with and without Mesial Temporal Sclerosis 
Epilepsia  2007;48(2):220-228.
Summary
Introduction
Quantitative measurements of T2 relaxation in the hippocampus for focus lateralization in mesial temporal lobe epilepsy (mTLE) are well established. Less is known to what degree such relaxation abnormalities also affect regions beyond the ipsilateral hippocampus. Therefore, the aim of this study was to characterize extent and distribution pattern of extrahippocampal relaxation abnormalities in TLE with (TLE-MTS) and without MRI evidence of mesial-temporal sclerosis (TLE-no).
Methods
Double spin echo images (TE1/2: 20/80 ms) acquired in 24 TLE-MTS and 18 TLE-no were used to calculate relaxation rate maps. These maps were analyzed by SPM2 and by selecting regions of interest (ROI) in the hippocampus and several extrahippocampal brain regions.
Results
In TLE-MTS, the results of the SPM and ROI analysis were in good agreement and showed the most severe relaxation rate decreases in the ipsilateral hippocampus but also in other ipsilateral temporal regions, orbitofrontal, and parietal regions and to a lesser degree in contralateral frontal regions. The relaxation rate decreases in TLE-no were confined to small regions in the ipsilateral anterior inferior and medial temporal lobe in the SPM analysis while ROI analysis showed additional regions in the ipsilateral hippocampus, amygdala, and anterior cingulate.
Conclusion
TLE-MTS showed extensive, widespread but predominantly ipsilateral temporal and also extratemporal T2 relaxation rate decreases. In contrast, the findings of the SPM and ROI analyses in TLE-no suggested that if relaxation rate decreases are present, they are less uniform and generally milder than in TLE-MTS. This further supports the hypothesis that TLE-no is a distinct clinicopathological entity from TLE-MTS and probably heterogeneous in itself.
doi:10.1111/j.1528-1167.2006.00916.x
PMCID: PMC2744642  PMID: 17295614
TLE; Extratemporal; Voxel-based; Mesiotemporal sclerosis; Normal MRI; Relaxation rate
14.  Memory reorganization following anterior temporal lobe resection: a longitudinal functional MRI study 
Brain  2013;136(6):1889-1900.
Anterior temporal lobe resection controls seizures in 50–60% of patients with intractable temporal lobe epilepsy but may impair memory function, typically verbal memory following left, and visual memory following right anterior temporal lobe resection. Functional reorganization can occur within the ipsilateral and contralateral hemispheres. We investigated the reorganization of memory function in patients with temporal lobe epilepsy before and after left or right anterior temporal lobe resection and the efficiency of postoperative memory networks. We studied 46 patients with unilateral medial temporal lobe epilepsy (25/26 left hippocampal sclerosis, 16/20 right hippocampal sclerosis) before and after anterior temporal lobe resection on a 3 T General Electric magnetic resonance imaging scanner. All subjects had neuropsychological testing and performed a functional magnetic resonance imaging memory encoding paradigm for words, pictures and faces, testing verbal and visual memory in a single scanning session, preoperatively and again 4 months after surgery. Event-related analysis revealed that patients with left temporal lobe epilepsy had greater activation in the left posterior medial temporal lobe when successfully encoding words postoperatively than preoperatively. Greater pre- than postoperative activation in the ipsilateral posterior medial temporal lobe for encoding words correlated with better verbal memory outcome after left anterior temporal lobe resection. In contrast, greater postoperative than preoperative activation in the ipsilateral posterior medial temporal lobe correlated with worse postoperative verbal memory performance. These postoperative effects were not observed for visual memory function after right anterior temporal lobe resection. Our findings provide evidence for effective preoperative reorganization of verbal memory function to the ipsilateral posterior medial temporal lobe due to the underlying disease, suggesting that it is the capacity of the posterior remnant of the ipsilateral hippocampus rather than the functional reserve of the contralateral hippocampus that is important for maintaining verbal memory function after anterior temporal lobe resection. Early postoperative reorganization to ipsilateral posterior or contralateral medial temporal lobe structures does not underpin better performance. Additionally our results suggest that visual memory function in right temporal lobe epilepsy is affected differently by right anterior temporal lobe resection than verbal memory in left temporal lobe epilepsy.
doi:10.1093/brain/awt105
PMCID: PMC3673465  PMID: 23715092
temporal lobe epilepsy; functional MRI; verbal memory; visual memory; anterior temporal lobe resection
15.  Preoperative amygdala fMRI in temporal lobe epilepsy 
Epilepsia  2009;50(2):217-227.
Purpose:
Anterior temporal lobe resections (ATLR) benefit 70% of patients with refractory mesial temporal lobe epilepsy (TLE), but may be complicated by emotional disturbances. We used functional magnetic resonance imaging (fMRI) to investigate the role of the amygdala in processing emotions in TLE and whether this may be a potential preoperative predictive marker for emotional disturbances following surgery.
Methods:
We studied 54 patients with refractory mesial TLE due to hippocampal sclerosis (28 right, 26 left) and 21 healthy controls using a memory encoding fMRI paradigm, which included viewing fearful and neutral faces. Twenty-one TLE patients (10 left, 11 right) subsequently underwent ATLR. Anxiety and depression were assessed preoperatively and 4 months postoperatively using the Hospital Anxiety and Depression Scale.
Results:
On viewing fearful faces, healthy controls demonstrated left lateralized, while right TLE patients showed bilateral amygdala activation. Left TLE patients had significantly reduced activation in left and right amygdalae compared to controls and right TLE patients. In right TLE patients, left and right amygdala activation was significantly related to preoperative anxiety and depression levels, and preoperative right amygdala activation correlated significantly with postoperative change of anxiety and depression scores, characterized by greater increases in anxiety and depression in patients with greater preoperative activation. No such correlations were seen for left TLE patients.
Discussion:
The fearful face fMRI paradigm is a reliable method for visualizing amygdala activation in controls and patients with mesial TLE. Activation of the right amygdala preoperatively was predictive of emotional disturbances following right ATLR.
doi:10.1111/j.1528-1167.2008.01739.x
PMCID: PMC2905610  PMID: 18717711
Temporal lobe epilepsy; fMRI; Emotion; Amygdala.
16.  Neural circuitry of emotional face processing in autism spectrum disorders 
Background
Autism spectrum disorders (ASD) are associated with severe impairments in social functioning. Because faces provide nonverbal cues that support social interactions, many studies of ASD have examined neural structures that process faces, including the amygdala, ventromedial prefrontal cortex and superior and middle temporal gyri. However, increases or decreases in activation are often contingent on the cognitive task. Specifically, the cognitive domain of attention influences group differences in brain activation. We investigated brain function abnormalities in participants with ASD using a task that monitored attention bias to emotional faces.
Methods
Twenty-four participants (12 with ASD, 12 controls) completed a functional magnetic resonance imaging study while performing an attention cuing task with emotional (happy, sad, angry) and neutral faces.
Results
In response to emotional faces, those in the ASD group showed greater right amygdala activation than those in the control group. A preliminary psychophysiological connectivity analysis showed that ASD participants had stronger positive right amygdala and ventromedial prefrontal cortex coupling and weaker positive right amygdala and temporal lobe coupling than controls. There were no group differences in the behavioural measure of attention bias to the emotional faces.
Limitations
The small sample size may have affected our ability to detect additional group differences.
Conclusion
When attention bias to emotional faces was equivalent between ASD and control groups, ASD was associated with greater amygdala activation. Preliminary analyses showed that ASD participants had stronger connectivity between the amygdala ventromedial prefrontal cortex (a network implicated in emotional modulation) and weaker connectivity between the amygdala and temporal lobe (a pathway involved in the identification of facial expressions, although areas of group differences were generally in a more anterior region of the temporal lobe than what is typically reported for emotional face processing). These alterations in connectivity are consistent with emotion and face processing disturbances in ASD.
doi:10.1503/jpn.090085
PMCID: PMC2834792  PMID: 20184808
17.  Imaging memory in temporal lobe epilepsy: predicting the effects of temporal lobe resection 
Brain  2010;133(4):1186-1199.
Functional magnetic resonance imaging can demonstrate the functional anatomy of cognitive processes. In patients with refractory temporal lobe epilepsy, evaluation of preoperative verbal and visual memory function is important as anterior temporal lobe resections may result in material specific memory impairment, typically verbal memory decline following left and visual memory decline after right anterior temporal lobe resection. This study aimed to investigate reorganization of memory functions in temporal lobe epilepsy and to determine whether preoperative memory functional magnetic resonance imaging may predict memory changes following anterior temporal lobe resection. We studied 72 patients with unilateral medial temporal lobe epilepsy (41 left) and 20 healthy controls. A functional magnetic resonance imaging memory encoding paradigm for pictures, words and faces was used testing verbal and visual memory in a single scanning session on a 3T magnetic resonance imaging scanner. Fifty-four patients subsequently underwent left (29) or right (25) anterior temporal lobe resection. Verbal and design learning were assessed before and 4 months after surgery. Event-related functional magnetic resonance imaging analysis revealed that in left temporal lobe epilepsy, greater left hippocampal activation for word encoding correlated with better verbal memory. In right temporal lobe epilepsy, greater right hippocampal activation for face encoding correlated with better visual memory. In left temporal lobe epilepsy, greater left than right anterior hippocampal activation on word encoding correlated with greater verbal memory decline after left anterior temporal lobe resection, while greater left than right posterior hippocampal activation correlated with better postoperative verbal memory outcome. In right temporal lobe epilepsy, greater right than left anterior hippocampal functional magnetic resonance imaging activation on face encoding predicted greater visual memory decline after right anterior temporal lobe resection, while greater right than left posterior hippocampal activation correlated with better visual memory outcome. Stepwise linear regression identified asymmetry of activation for encoding words and faces in the ipsilateral anterior medial temporal lobe as strongest predictors for postoperative verbal and visual memory decline. Activation asymmetry, language lateralization and performance on preoperative neuropsychological tests predicted clinically significant verbal memory decline in all patients who underwent left anterior temporal lobe resection, but were less able to predict visual memory decline after right anterior temporal lobe resection. Preoperative memory functional magnetic resonance imaging was the strongest predictor of verbal and visual memory decline following anterior temporal lobe resection. Preoperatively, verbal and visual memory function utilized the damaged, ipsilateral hippocampus and also the contralateral hippocampus. Memory function in the ipsilateral posterior hippocampus may contribute to better preservation of memory after surgery.
doi:10.1093/brain/awq006
PMCID: PMC2850579  PMID: 20157009
functional MRI; verbal and visual memory; temporal lobe epilepsy; anterior temporal lobe resection
18.  Early Activation of Ventral Hippocampus and Subiculum during Spontaneous Seizures in a Rat Model of Temporal Lobe Epilepsy 
The Journal of Neuroscience  2013;33(27):11100-11115.
Temporal lobe epilepsy is the most common form of epilepsy in adults. The pilocarpine-treated rat model is used frequently to investigate temporal lobe epilepsy. The validity of the pilocarpine model has been challenged based largely on concerns that seizures might initiate in different brain regions in rats than in patients. The present study used 32 recording electrodes per rat to evaluate spontaneous seizures in various brain regions including the septum, dorsomedial thalamus, amygdala, olfactory cortex, dorsal and ventral hippocampus, substantia nigra, entorhinal cortex, and ventral subiculum. Compared with published results from patients, seizures in rats tended to be shorter, spread faster and more extensively, generate behavioral manifestations more quickly, and produce generalized convulsions more frequently. Similarities to patients included electrographic waveform patterns at seizure onset, variability in sites of earliest seizure activity within individuals, and variability in patterns of seizure spread. Like patients, the earliest seizure activity in rats was recorded most frequently within the hippocampal formation. The ventral hippocampus and ventral subiculum displayed the earliest seizure activity. Amygdala, olfactory cortex, and septum occasionally displayed early seizure latencies, but not above chance levels. Substantia nigra and dorsomedial thalamus demonstrated consistently late seizure onsets, suggesting their unlikely involvement in seizure initiation. The results of the present study reveal similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and pilocarpine-treated rats that support the model's validity.
doi:10.1523/JNEUROSCI.0472-13.2013
PMCID: PMC3718374  PMID: 23825415
19.  Amygdala damage affects event-related potentials for fearful faces at specific time windows 
Human brain mapping  2010;31(7):1089-1105.
The amygdala is known to influence processing of threat-related stimuli in distant brain regions, including visual cortex. The time-course of these distant influences is unknown, although this information is important for resolving debates over likely pathways mediating an apparent rapidity in emotional processing. To address this, we recorded event-related-potentials (ERPs) to seen fearful face expressions, in pre-operative patients with medial temporal lobe epilepsy who had varying degrees of amygdala pathology, plus healthy volunteers. We found that amygdala damage diminished ERPs for fearful versus neutral faces within the P1 time-range, ~100-150msec, and for a later component at ~500-600msec. Individual severity of amygdala damage determined the magnitude of both these effects, consistent with a causal amygdala role. By contrast, amygdala damage did not affect explicit perception of fearful expressions, nor a distinct emotional ERP effect at 150-250msec. These results demonstrate two distinct time-points at which the amygdala influences fear processing. The data also demonstrate that while not all aspects of expression processing are disrupted by amygdala damage, there is a crucial impact on an early P1 component. These findings are consistent with the existence of multiple processing stages or routes for fearful faces that vary in their dependence on amygdala function.
doi:10.1002/hbm.20921
PMCID: PMC3173845  PMID: 20017134
ERP; medial temporal lobe epilepsy; emotion; P1; late-P3; SPM5
20.  Amygdala Damage Affects Event-Related Potentials for Fearful Faces at Specific Time Windows 
Human Brain Mapping  2009;31(7):1089-1105.
The amygdala is known to influence processing of threat-related stimuli in distant brain regions, including visual cortex. The time-course of these distant influences is unknown, although this information is important for resolving debates over likely pathways mediating an apparent rapidity in emotional processing. To address this, we recorded event-related potentials (ERPs) to seen fearful face expressions, in preoperative patients with medial temporal lobe epilepsy who had varying degrees of amygdala pathology, plus healthy volunteers. We found that amygdala damage diminished ERPs for fearful versus neutral faces within the P1 time-range, ∼100–150 ms, and for a later component at ∼500–600 ms. Individual severity of amygdala damage determined the magnitude of both these effects, consistent with a causal amygdala role. By contrast, amygdala damage did not affect explicit perception of fearful expressions nor a distinct emotional ERP effect at 150–250 ms. These results demonstrate two distinct time-points at which the amygdala influences fear processing. The data also demonstrate that while not all aspects of expression processing are disrupted by amygdala damage, there is a crucial impact on an early P1 component. These findings are consistent with the existence of multiple processing stages or routes for fearful faces that vary in their dependence on amygdala function. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc.
doi:10.1002/hbm.20921
PMCID: PMC3173845  PMID: 20017134
ERP; medial temporal lobe epilepsy; emotion; P1; late-P3; SPM5
21.  Reduction in temporal N-acetylaspartate and creatine (or choline) ratio in temporal lobe epilepsy: does this 1H-magnetic resonance spectroscopy finding mean poor seizure control? 
BACKGROUND—Proton magnetic resonance spectroscopy (1H-MRS) is a potentially useful tool in the in vivo investigation of brain metabolites in intractable temporal lobe epilepsy (TLE). Focal N-acetylaspartatate (NAA) reductions have been correlated with mesial temporal sclerosis (MTS) in surgically resected epileptogenic foci.
OBJECTIVE—To evaluate the abnormalities in the metabolites NAA, creatine+ phosphocreatine (Cr), and choline containing compounds (Cho) in the temporal lobe of medically refractory patients with temporal lobe epilepsy, seizure free patients with temporal lobe epilepsy, and normal controls.
PATIENTS AND METHODS—Ten refractory patients, 12 seizure free patients with temporal lobe epilepsy, and 10 age matched normal controls were studied by 1H-magnetic resonance spectroscopy. All patients had consistently unilateral temporal EEG abnormalities and a normal brain MRI. Proton MR spectra were obtained from an 8 ml volume in the medial temporal lobes in patients with temporal lobe epilepsy (ipsilateral to EEG foci) and the normal controls. The signals measured were expressed in terms of NAA/Cr, NAA/Cho, and Cho/Cr.
RESULTS—When compared with seizure free patients with temporal lobe epilepsy and normal controls, the 10 refractory patients with temporal lobe epilepsy had a lower mean (SEM) NAA/Cr ratio (1.65(0.53) v 2.62 (0.60), and 2.66 (0.73); p<0.002 and p<0.006) and a lower mean NAA/Cho ratio (1.59 (0.79) v 2.83 (1.33) and 2.58(0.67); p<0.02 andp<0.007). Furthermore, the two patients showing the lowest NAA/Cr ratios (1.47 and 1.73) in the seizure free group had had a past period of poor seizure control.
CONCLUSIONS—There were reduced temporal NAA/Cr and NAA/Cho ratios, suggesting neuronal loss or damage, associated with past or present poor seizure control in the patients with temporal lobe epilepsy, but it does not exclude the possibility of a future complete seizure control (seizure free patients with temporal lobe epilepsy at the time of 1H-MRS). This study warrants further 1H-MRS investigation with a larger series of patients with temporal lobe epilepsy.


PMCID: PMC2170285  PMID: 9771777
22.  Working memory network plasticity after anterior temporal lobe resection: a longitudinal functional magnetic resonance imaging study 
Brain  2014;137(5):1439-1453.
Temporal lobe surgery can control seizures in drug-resistant epilepsy, but its impact on working memory is poorly understood. Using functional MRI, Stretton et al. reveal improvements in working memory post-surgery, which depend upon the functional capacity of the hippocampal remnant and the functional reserve of the contralateral hippocampus.
Working memory is a crucial cognitive function that is disrupted in temporal lobe epilepsy. It is unclear whether this impairment is a consequence of temporal lobe involvement in working memory processes or due to seizure spread to extratemporal eloquent cortex. Anterior temporal lobe resection controls seizures in 50–80% of patients with drug-resistant temporal lobe epilepsy and the effect of surgery on working memory are poorly understood both at a behavioural and neural level. We investigated the impact of temporal lobe resection on the efficiency and functional anatomy of working memory networks. We studied 33 patients with unilateral medial temporal lobe epilepsy (16 left) before, 3 and 12 months after anterior temporal lobe resection. Fifteen healthy control subjects were also assessed in parallel. All subjects had neuropsychological testing and performed a visuospatial working memory functional magnetic resonance imaging paradigm on these three separate occasions. Changes in activation and deactivation patterns were modelled individually and compared between groups. Changes in task performance were included as regressors of interest to assess the efficiency of changes in the networks. Left and right temporal lobe epilepsy patients were impaired on preoperative measures of working memory compared to controls. Working memory performance did not decline following left or right temporal lobe resection, but improved at 3 and 12 months following left and, to a lesser extent, following right anterior temporal lobe resection. After left anterior temporal lobe resection, improved performance correlated with greater deactivation of the left hippocampal remnant and the contralateral right hippocampus. There was a failure of increased deactivation of the left hippocampal remnant at 3 months after left temporal lobe resection compared to control subjects, which had normalized 12 months after surgery. Following right anterior temporal lobe resection there was a progressive increase of activation in the right superior parietal lobe at 3 and 12 months after surgery. There was greater deactivation of the right hippocampal remnant compared to controls between 3 and 12 months after right anterior temporal lobe resection that was associated with lesser improvement in task performance. Working memory improved after anterior temporal lobe resection, particularly following left-sided resections. Postoperative working memory was reliant on the functional capacity of the hippocampal remnant and, following left resections, the functional reserve of the right hippocampus. These data suggest that working memory following temporal lobe resection is dependent on the engagement of the posterior medial temporal lobes and eloquent cortex.
doi:10.1093/brain/awu061
PMCID: PMC3999723  PMID: 24691395
working memory; temporal lobe surgery; epilepsy; functional MRI
23.  Evaluation of subcortical grey matter abnormalities in patients with MRI-negative cortical epilepsy determined through structural and tensor magnetic resonance imaging 
BMC Neurology  2014;14:104.
Background
Although many studies have found abnormalities in subcortical grey matter (GM) in patients with temporal lobe epilepsy or generalised epilepsies, few studies have examined subcortical GM in focal neocortical seizures. Using structural and tensor magnetic resonance imaging (MRI), we evaluated subcortical GM from patients with extratemporal lobe epilepsy without visible lesion on MRI. Our aims were to determine whether there are structural abnormalities in these patients and to correlate the extent of any observed structural changes with clinical characteristics of disease in these patients.
Methods
Twenty-four people with epilepsy and 29 age-matched normal subjects were imaged with high-resolution structural and diffusion tensor MR scans. The patients were characterised clinically by normal brain MRI scans and seizures that originated in the neocortex and evolved to secondarily generalised convulsions. We first used whole brain voxel-based morphometry (VBM) to detect density changes in subcortical GM. Volumetric data, values of mean diffusivity (MD) and fractional anisotropy (FA) for seven subcortical GM structures (hippocampus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, thalamus and amygdala) were obtained using a model-based segmentation and registration tool. Differences in the volumes and diffusion parameters between patients and controls and correlations with the early onset and progression of epilepsy were estimated.
Results
Reduced volumes and altered diffusion parameters of subcortical GM were universally observed in patients in the subcortical regions studied. In the patient-control group comparison of VBM, the right putamen, bilateral nucleus accumbens and right caudate nucleus of epileptic patients exhibited a significantly decreased density Segregated volumetry and diffusion assessment of subcortical GM showed apparent atrophy of the left caudate nucleus, left amygdala and right putamen; reduced FA values for the bilateral nucleus accumbens; and elevated MD values for the left thalamus, right hippocampus and right globus pallidus A decreased volume of the nucleus accumbens consistently related to an early onset of disease. The duration of disease contributed to the shrinkage of the left thalamus.
Conclusions
Patients with neocortical seizures and secondary generalisation had smaller volumes and microstructural anomalies in subcortical GM regions. Subcortical GM atrophy is relevant to the early onset and progression of epilepsy.
doi:10.1186/1471-2377-14-104
PMCID: PMC4080585  PMID: 24885823
Subcortical grey matter; Neocortical epilepsy; Volumetry; Diffusion tensor imaging
24.  Microsurgical Anatomy of the Temporal Lobe and Its Implications on Temporal Lobe Epilepsy Surgery 
Objective. We review the neuroanatomical aspects of the temporal lobe related to the temporal lobe epilepsy. The neuronal, the ventricular, and the vascular structures are demonstrated. Methods. The previous articles published from the laboratory of the senior author are reviewed. Results. The temporal lobe has four surfaces. The medial surface has a complicated microanatomy showing close relation to the intraventricular structures, such as the amygdala or the hippocampus. There are many white matter bundles in the temporal lobe showing relation to the extra- and intraventricular structures. The surgical approaches commonly performed to treat temporal lobe epilepsy are discussed under the light of these data. Conclusion. A thorough knowledge of the microanatomy is necessary in cortical, subcortical, and intraventricular structures of the temporal lobe to achieve better results.
doi:10.1155/2012/769825
PMCID: PMC3420566  PMID: 22957242
25.  Hemifacial motor and crying seizures of temporal lobe onset: case report and review of electro‐clinical localisation 
Objective
To report a case of temporal lobe epilepsy with clinical presentation of paroxysmal episodes of “tightness” over the right hemiface, and ictal crying, and review electroclinical localisation of this phenomenon.
Methods
Clinical semiology, neurophysiological localising tests, and epilepsy surgery outcome are reported in a subject presenting with paroxysmal right hemifacial movements and ictal crying. Pertinent past reports of somato‐motor signs and ictal crying in temporal lobe epilepsy are reviewed and the findings correlated with proposed human facial cortical representation.
Results
Simple partial seizures caused by temporal lobe epilepsy presented with right sided tonic facial movements and ictal crying. Intracranial EEG monitoring documented a left medial temporal onset of seizures that remained asymptomatic until they propagated to the left cingulate region. Anterior temporal lobectomy with resection of the amygdala and anterior hippocampus resulted in cessation of seizures.
Conclusions
This is a rare example of epileptic seizures of medial temporal onset presenting with isolated somato‐motor manifestations and ictal crying. Anatomical‐electrical‐clinical correlations with cortical regions controlling facial movements were highly suggestive that this case represents secondary activation of “emotional” motor cortex M3 and M4 (rostral and caudal cingulate motor cortex), giving rise to focal hemifacial movements and ictal crying.
doi:10.1136/jnnp.2005.062554
PMCID: PMC2117386  PMID: 16361607
temporal lobe epilepsy; crying; cingulate gyrus

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