Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

Allen, Luke; Vos, Sjoerd B.; Kumar, Rajesh; Ogren, Jennifer A.; Harper, Rebecca K.; Winston, Gavin P.; Balestrini, Simona; Wandschneider, Britta; Scott, Catherine; Ourselin, Sébastien; Duncan, John S.; Lhatoo, Samden D.; Harper, Ronald M.; Diehl, Beate

doi:10.1111/epi.14689

Cited by 56 publications

(82 citation statements)

References 42 publications

(73 reference statements)

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“…; Allen et al . ; Li et al . ), changes in cerebellar actvity are associated with seizure events (Niedermeyer & Uematsu, ; Mitra & Snider, ; Kandel & Buzsaki, ; Blumenfeld et al .…”

Section: Discussionmentioning

confidence: 99%

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Streng

Krook-Magnuson

2019

The Journal of Physiology

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Key pointsr On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy.r In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures.r On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures.r Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity.Abstract Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells -the fastigial nucleus -in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest Martha Streng received a BA in Neuroscience and Behaviour from Mount Holyoke College and a PhD in Neuroscience from the University of Minnesota, Twin Cities, where she studied the encoding of motor predictive and feedback information by Purkinje cells during online motor control tasks. Her current research focuses on the characterization of cerebellar circuitry and output channels in health and disease. that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

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“…; Allen et al . ; Li et al . ), changes in cerebellar actvity are associated with seizure events (Niedermeyer & Uematsu, ; Mitra & Snider, ; Kandel & Buzsaki, ; Blumenfeld et al .…”

Section: Discussionmentioning

confidence: 99%

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Streng

Krook-Magnuson

2019

The Journal of Physiology

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“…Furthermore, it is known that increased brain age predicts mortality risk [37]. Given that epilepsy is associated with an increased risk of sudden death [38], possibly related to specific brain structures essential for cardiorespiratory recovery [39], future application of brain age might be beneficial to identify patients at high risk of sudden death.…”

Section: Discussionmentioning

confidence: 99%

Neuroimaging-based brain-age prediction in diverse forms of epilepsy: a signature of psychosis and beyond

et al. 2019

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Epilepsy is a diverse brain disorder, and the pathophysiology of its various forms and comorbidities is largely unknown. A recent machine learning method enables us to estimate an individual's "brain-age" from MRI; this brain-age prediction is expected as a novel individual biomarker of neuropsychiatric disorders. The aims of this study were to estimate the brain-age for various categories of epilepsy and to evaluate clinical discrimination by brain-age for (1) the effect of psychosis on temporal lobe epilepsy (TLE), (2) psychogenic nonepileptic seizures (PNESs) from MRI-negative epilepsies, and (3) progressive myoclonic epilepsy (PME) from juvenile myoclonic epilepsy (JME). In total, 1196 T1-weighted MRI scans from healthy controls (HCs) were used to build a brain-age prediction model with support vector regression. Using the model, we calculated the brain-predicted age difference (brain-PAD: predicted age-chronological age) of the HCs and 318 patients with epilepsy. We compared the brain-PAD values based on the research questions. As a result, all categories of patients except for extra-temporal lobe focal epilepsy showed a significant increase in brain-PAD. TLE with hippocampal sclerosis presented a significantly higher brain-PAD than several other categories. The mean brain-PAD in TLE with interictal psychosis was 10.9 years, which was significantly higher than TLE without psychosis (5.3 years). PNES showed a comparable mean brain-PAD (10.6 years) to that of epilepsy patients. PME had a higher brain-PAD than JME (22.0 vs. 9.3 years). In conclusion, neuroimaging-based brain-age prediction can provide novel insight into or clinical usefulness for the diverse symptoms of epilepsy.

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“…Other examples of degeneration over longer anatomical distances exist, however. In the case of epilepsy, which is thought to be driven primarily by neocortical structures, cerebellar atrophy is a common finding (Hermann et al, 2005; Kros et al, 2015; Allen et al, 2019). This leads to speculation as to whether cerebellar volume changes in certain etiologies of ASD reflect network disruption in addition to those with primary cerebellar pathogenesis (see above discussion).…”

Section: Interregional Connectivity and The Cerebellummentioning

confidence: 99%

Functional Outcomes of Cerebellar Malformations

Gill

Sillitoe

2019

Front. Cell. Neurosci.

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The cerebellum is well-established as a primary center for controlling sensorimotor functions. However, recent experiments have demonstrated additional roles for the cerebellum in higher-order cognitive functions such as language, emotion, reward, social behavior, and working memory. Based on the diversity of behaviors that it can influence, it is therefore not surprising that cerebellar dysfunction is linked to motor diseases such as ataxia, dystonia, tremor, and Parkinson’s disease as well to non-motor disorders including autism spectrum disorders (ASD), schizophrenia, depression, and anxiety. Regardless of the condition, there is a growing consensus that developmental disturbances of the cerebellum may be a central culprit in triggering a number of distinct pathophysiological processes. Here, we consider how cerebellar malformations and neuronal circuit wiring impact brain function and behavior during development. We use the cerebellum as a model to discuss the expanding view that local integrated brain circuits function within the context of distributed global networks to communicate the computations that drive complex behavior. We highlight growing concerns that neurological and neuropsychiatric diseases with severe behavioral outcomes originate from developmental insults to the cerebellum.

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Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

Cited by 56 publications

References 42 publications

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Neuroimaging-based brain-age prediction in diverse forms of epilepsy: a signature of psychosis and beyond

Functional Outcomes of Cerebellar Malformations

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