Denervation and reinnervation of amygdala neurons in drug-resistant temporal lobe epilepsy (2023)

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Denervation and reinnervation of amygdala neurons in drug-resistant temporal lobe epilepsy (1)

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Epilepsy Curr.March 2004; 4(2): 78–79.



Asla Pitkänen, M.D., Ph.D.

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Cytopathology of amygdala neurons in human temporal lobe epilepsy

Aliashkevich AF, Yilmazer-Hanke D, Van Roost D, Mundhenk B, Schramm J, Blumcke I.

Acta Neuropathol 2003; 106:99-106

The amygdala complex contributes substantially to the generation and propagation of focal seizures in patients with temporal lobe epilepsy (TLE). However, a cellular substrate for increased excitability in the human amygdala remains to be identified. We analyzed the three-dimensional morphology of 264 neurons from different subregions of the amygdala complex obtained from 17 en bloc surgical specimens using Lucifer Yellow (LY) intracellular injection and confocal laser scanning microscopy. Autopsy specimens from unaffected individuals (n =3? 20 neurons) served as controls. We identified spine-laden, spine-sparse, and spiny cells in the lateral, basal, accessory basal, and granule nuclei. Semiquantitative analysis shows significant changes in nerve body size, dendrite number and spine density in samples from epileptic patients compared to controls. Neuronal bodies in the epilepsy group were smaller compared to controls (Pi< 0.01); neurons had fewer first-order dendrites (Pi< 0.01), while the maximum spine density per dendritic segment in these cells was increased in patients with TLE (Pi< 0.01). Dendritic alterations such as focal contractions or spine bifurcations were also present. These changes were consistent across amygdala subregions. The dendritic morphology of amygdala neurons in TLE patients indicates substantial changes in synaptic connectivity and would be compatible with altered neuronal circuits operating in the epileptic human amygdala. Although the morphological alterations differ from those described in hippocampal subregions of a similar cohort of TLE patients, they appear to reflect a characteristic pathological substrate associated with epileptiform activity/propagation within the amygdala.


The emotional center of the brain, the amygdala, is made up of 13 different nuclei and cortical areas. As previous studies show, amygdala damage is not uncommon in patients with temporal lobe epilepsy (TLE). According to magnetic resonance imaging (MRI) studies, it is present in ∼20% to 30% of patients with drug-resistant TLE and, based on autopsy studies, in 27% to 76% of TLE patients with hippocampal damage. What little is known about the distribution of neuronal loss and gliosis in the epileptic amygdala is largely based on Nissl staining and glial staining. These studies have consistently revealed that one of the most vulnerable regions of the amygdala is the lateral nucleus. Through the lateral nucleus, most of the sensory information from various cortical areas enters the amygdala and is further distributed to other amygdala areas through extensive intra-amygdala pathways. The other damaged area is the paracellular division of the nucleus accumbens, which is the amygdala portal to the hippocampus. In contrast to the epileptic hippocampus, no data are available on axonal or dendritic alterations in the epileptic amygdala in experimental or human epilepsy.

Aliashkevich and colleagues stained 264 amygdala neurons with a fluorescent dye, Lucifer Yellow, in 250-μm-thick slices obtained from 17 patients who had drug-resistant TLE. The majority of neurons were in the lateral nucleus (n= 169), but the authors also successfully paid neurons in the basal (n= 81), auxiliary basic (n= 7), and granular core (n= 7, corresponding to the medial aspect of the paraelastic nucleus in monkey and human amygdala). Thus, amygdala nuclei, which are known to be damaged in the epileptic brain, were all included in the present analysis. Data from epileptic brains were compared with three autopsy controls. Patients had a mean of 5.3 seizures/month, mean age at onset of epilepsy was 13.8 years, and mean disease duration was 19.8 years. All patients had complex partial seizures. Unfortunately, no details were given about the clinical symptoms of the seizures or the depth electrode recordings, and therefore the possible involvement of the amygdala in the initiation of seizures is unknown. No description of the MRI findings of the tonsils or data on the occurrence of tonsillar lesions in routine pathology was given. In contrast, the authors report that 15 of 17 patients had Ammon's horn sclerosis, one had dual pathology consisting of a dysembryoplastic neuroepithelial tumor in the superior temporal gyrus cortex and hippocampal sclerosis, and one had diffuse gliosis in cortical and subcortical regions.

Analysis of the 3D reconstructed neurons revealed that the neurons in the epileptic amygdala were small and had fewer dendrites. The remaining dendrites appeared thicker and had several abnormalities, such as contractions, swelling of dendritic axons, and bifurcation of spines. As the authors speculated, the lack of dendritic branching could be related to the lack of afferent inputs. There are no data on epileptic amygdala deactivation occurring as a result of atrophy of brain regions supplying inputs to the amygdala. One can only speculate whether, for example, damage to the perirhinal and entorhinal cortex, or the hippocampus, may have reduced the number of inputs to spiny neurons in the lateral and basal nuclei, which were included in the analysis. Histopathological analysis revealed the occurrence of hippocampal damage in most of the patients. In a group of chronic patients such as this, it is likely that a significant proportion of patients would also have damage to cortical areas of the parahippocampus, as suggested by MRI studies from the recent literature, and thus a reduced number of projections to the amygdala.

Studies on mossy fiber sprouting in the dentate gyrus have revealed that axonal sprouting is associated with an increased density of granule cell spines. Currently, no single study has demonstrated axonal sprouting in the epileptic amygdala. In contrast to the hippocampus, where mossy fiber sprouting can be easily demonstrated by Timm staining or dynorphin immunohistochemistry, no reliable marker can demonstrate axonal sprouting in the amygdala tracts. The increase in spine density from 1.8 to 2.9 spines/10 μm in the amygdala could be related to increased axonal sprouting associated with activity-dependent plasticity in the amygdala. Considering that the vast majority of patients had hippocampal pathology possibly related to mossy fiber sprouting, the present data support the idea that reorganization of neuronal circuits is not limited to the hippocampus in drug-resistant TLE patients.

Perhaps one of the most striking findings of the study was the variability of abnormalities in the dendritic axons, including nodular varices, focal swellings or contractions of the dendritic axon, and spine branches. As the authors suggest, these abnormalities could be related to changes in microtubule arrangements, accumulation of cytoskeletal filaments, or increased numbers of mitochondria. These data are of interest as they relate to recent microarray data from animals subjected to prolonged chemically or electrically induced seizures. The array data show that the expression of many of the genes that mediate structural alterations or reorganization of the cell cytoskeleton is altered. Whether these alterations persist in chronic status epilepticus associated with frequent, spontaneous seizures is a new and interesting area of ​​research.

The study by Aliashkevich and colleagues provides the first, and hopefully not the last, analysis of cellular morphology in the epileptic human amygdala. As the data show, there are many similarities with hippocampal pathology. This work is an important addition to the ever-expanding list of studies showing that neuronal pathology extends beyond the hippocampus in drug-resistant TLE. It is time to focus our microscope on regions outside the hippocampus in the search for neural substrates of epileptogenesis and imagery in human TLE. The almond is an excellent candidate.

Articles fromEpileptic currentsprovided here courtesy ofAmerican Epilepsy Society


How does epilepsy affect the amygdala? ›

Thus, both clinical findings and animal studies indicate that the amygdala plays a prominent role in the pathogenesis and the symptomatology of epilepsy. The basolateral region of the amygdala appears to be most susceptible to seizure generation.

What is an example of forced thinking? ›

Some persons can hear a song on the radio and part of the tune can sometimes get stuck into a person's brain for a while - even days. That's a kind of forced thinking (my view).

Can epilepsy be triggered by emotions? ›

Stress, anxiety, and other mood disorders can trigger seizures, but these are fairly common among people with epilepsy. If you are frequently stressed, talk to your physician or a mental health professional to see if you have a treatable mood disorder or to discuss ways to lower your stress levels.

What is temporal epilepsy? ›

Temporal lobe epilepsy (TLE) is epilepsy that starts in the temporal lobe area of your brain. You have two temporal lobes, one on each side of your head behind your temples (by your ears and in alignment with your eyes). TLE is the most common localized (also called “focal”) type of epilepsy.

How does temporal lobe epilepsy affect the amygdala? ›

Emotional Recognition in Patients With Mesial Temporal Epilepsy Associated With Enlarged Amygdala. Background: Amygdalae play a central role in emotional processing by interconnecting frontal cortex and other brain structures. Unilateral amygdala enlargement (AE) is associated with mesial temporal lobe epilepsy (mTLE).

What does the amygdala do in the temporal lobe? ›

Key areas of the temporal lobe

The temporal lobe contains a few noteworthy areas: The amygdala. Your amygdala manages emotions like fear and anxiety. It also contributes to how you feel when you get a reward and learning-related emotions.

What are examples of impulsive thoughts? ›

Impulsive thoughts are ideas or images that pop into one's mind spontaneously and are considered “taboo”. These thoughts can be as innocuous as slamming your face into a beautiful, expensive wedding cake or throwing your cell phone out of the window.

What does forceful thought mean? ›

: expressed in a way that is effective and that influences people's thoughts and ideas.

What is temporal lobe epilepsy personality? ›

He and other researchers found¹ that individuals with TLE presented with changes in personality and psychiatric symptoms, including affective dysregulation, irritability and impulsiveness, anxiety and obsessive-compulsive symptoms, paranoia, altered social interaction, grandiosity, schizophrenic-like symptoms, ...

Do epileptics lack empathy? ›

This meta-analysis included 28 studies. Adult patients with temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE) showed impairments in cognitive ToM and affective ToM/cognitive empathy compared to the healthy controls (HCs); no group differences were identified for affective empathy.

What mental illness can epilepsy cause? ›

Mental health issues such as anxiety and depression are common in people with epilepsy. In some cases, there may be links between a person's epilepsy and mental health. Possible links include how epilepsy affects their life, how their brain is affected, and their genetic or family history.

What is the best drug for temporal lobe epilepsy? ›

For patients with MTLE, the most effective AEDs are those used to treat focal epilepsies such as carbamazepine, oxcarbazepine, levetiracetam, lamotrigine, and topiramate. [41] These agents can be monotherapy or, more often, in combination to achieve adequate seizure freedom.

What triggers temporal lobe epilepsy? ›

  • Traumatic brain injury.
  • Infections such as encephalitis or meningitis. Or a history of such infections.
  • A process that causes scarring in a part of the temporal lobe called the hippocampus. This is known as gliosis.
  • Blood vessel malformations in the brain.
  • Stroke.
  • Brain tumors.
  • Genetic syndromes.
Apr 7, 2023

What is the most common cause of temporal lobe epilepsy? ›

The most common causes are:
  • Hippocampal sclerosis.
  • Infections.
  • Tumors.
  • Traumatic brain injury.
  • Vascular anomalies.
  • Genetic.
  • Cryptogenic.

Does epilepsy surgery remove amygdala? ›

Temporal lobectomy is the most common type of surgery for people with temporal lobe epilepsy. It removes a part of the anterior temporal lobe along with the amygdala and hippocampus. A temporal lobectomy leads to a significant reduction or complete seizure control about 70% to 80% of the time [4, 5].

What does temporal lobe epilepsy feel like? ›

A sudden sense of fear or joy. A feeling that what's happening has happened before, known as deja vu. A sudden or strange odor or taste. A rising sensation in the belly similar to being on a roller coaster.

Does temporal lobe epilepsy cause anger issues? ›

Temporal lobe epilepsy (TLE) and mood

So someone may experience unusual feelings of anger or anxiety and this may actually be a seizure in the temporal lobe. If it is a seizure then they will not be in control over those feelings. This can be difficult for other people to understand.

Does the temporal lobe contain the amygdala? ›

The temporal lobe subdivides further into the superior temporal lobe, the middle temporal lobe, and the inferior temporal lobe. It houses several critical brain structures including the hippocampus and the amygdala.

Where is the amygdala located temporal lobe? ›

The amygdala is located in the medial temporal lobe, just anterior to (in front of) the hippocampus. Similar to the hippocampus, the amygdala is a paired structure, with one located in each hemisphere of the brain.

What happens when the amygdala is damaged? ›

Acquired amygdala damage reliably impairs fear conditioning, and behavioural, physiological and (in humans and perhaps other species, subjective) responses to threats [6–9].

How do you disarm intrusive thoughts? ›

Five Tips to Stop Intrusive Thoughts
  1. Don't suppress the thought. ...
  2. Recognize the difference between thought and reality. ...
  3. Identify the triggers. ...
  4. Implement a positive change into your daily routine. ...
  5. Talk it out and don't rule out therapy.
May 18, 2020

What are forced thoughts called? ›

They're called “intrusive thoughts” and nearly everyone has them from time to time. They can range from random images to disturbing and violent ideas like punching someone in the face or hurting yourself.

What is dark impulsivity? ›

It means acting solely on your emotions and “in the spur of the moment” rather than being able to contain your need for immediate gratification, often employing emotional reasoning and without thoroughly regarding the consequences of your actions.

What is the most common intrusive thought? ›

Doubts are one of the most common types of intrusive thoughts. The doubts can be about big or small aspects of your life. For example, intrusive thoughts might cause you to question your relationship or sexual orientation.

What medication is used for impulse control in adults? ›

The medication naltrexone reduces drug cravings in people with substance use disorders. Some people with impulse control disorders may benefit from this medication, and it may also reduce the craving or urge to engage in an impulsive behavior.

What is thought blocking? ›

Thought blocking is defined as any experience where a person suddenly finds themselves unable to think, speak, or move in response to events that are happening around them. This may happen at any time. The average duration of episodes is between a few seconds to a minute or longer.

What is an extraneous thought? ›

Extraneous things are not relevant or essential to the situation you are involved in or the subject you are talking about.

What is extremely violent intrusive thoughts? ›

Having unwanted thoughts with violent content is a totally normal part of how the brain works and people with and without OCD have these thoughts. People without OCD are more likely to assume that mechanisms in the brain for controlling impulses can be trusted to do their job.

How severe is temporal lobe epilepsy? ›

Overall, the prognosis for people with drug-resistant medial temporal lobe epilepsy includes a higher risk for memory and mood problems, lower quality of life, and an increased risk for sudden unexpected death in epilepsy (SUDEP).

What are the behavioral changes in temporal lobe epilepsy? ›

These changes include alterations in sexual behavior, religiosity, and a tendency toward extensive, and in some cases compulsive, writing and drawing.

What personality changes occur due to epilepsy? ›

Emotional lability is also reported. Sexuality and libido are typically decreased, but fetishism, transvestism, exhibitionism, and hypersexual episodes also occur. Concerns over morality may be lacking or exaggerated. Patients may be irritable and aggressive or timid and apathetic.

What do people with epilepsy struggle with? ›

People with epilepsy tend to have more physical problems (such as fractures and bruising from injuries related to seizures), as well as higher rates of psychological conditions, including anxiety and depression.

What changes in personality with epilepsy? ›

The most common mood disorders in people with epilepsy are major depression and dysthymia. Some people have milder forms of depression that may also affect quality of life and respond to treatment. Anxiety, while not technically a mood disorder, is another common emotion that occurs more often in people with epilepsy.

Is epilepsy a form of brain damage? ›

Although scientists and clinicians have long known that prolonged seizures, a condition referred to as "status epilepticus," kill brain cells, surprisingly little scientific evidence exists to support the notion that individual seizures do damage.

Is temporal lobe epilepsy a mental illness? ›

TLE is among all epilepsies the most frequently associated with psychiatric comorbidity. Anxiety, depression, and interictal dysphoria are recurrent psychiatric disorders in pediatric patients with TLE. In addition, these alterations are often combined with cognitive, learning, and behavioral impairment.

What are the five neuropsychiatric conditions of epilepsy? ›

Psychiatric Disorders Associated With Epilepsy
  • Sections Psychiatric Disorders Associated With Epilepsy.
  • Psychotic Disorders.
  • Bipolar Affective Disorders.
  • Suicidal Behaviors.
  • Anxiety Disorders.
  • Personality Disorders.
  • Attention-Deficit/Hyperactivity Disorder.
  • Psychotropic Effects of Antiseizure Medications.
Jul 27, 2022

What are the new drugs for temporal lobe epilepsy? ›

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine is a newer AED; it was approved as an adjunctive therapy and a crossover monotherapy for partial seizures. It also blocks sodium channels during sustained, rapid, repetitive neuronal firing.

What vitamin helps the brain with epilepsy? ›

The only vitamin deficiency known to cause or worsen seizures is a deficiency of vitamin B6 (pyridoxine). This deficiency occurs mainly in newborns and infants and causes seizures that are hard to control.

Does temporal lobe epilepsy get worse? ›

It Goes Downhill From Here but Do Not Despair: Mesial Temporal Lobe Epilepsy Is a Progressive Disease, but It Can Be Benign - PMC.

Can temporal lobe damage reversed? ›

While temporal lobe damage cannot be reversed, functions affected by the damage can be reorganized and relearned by healthy regions of the brain. The brain possesses a dynamic ability to heal itself and allow undamaged portions of the brain to take over control of damaged functions called neuroplasticity.

Is temporal lobe epilepsy progressive? ›

Temporal lobe epilepsy is a progressive neurologic disorder.

What is the prognosis for temporal lobe epilepsy? ›

About 47–60% of patients become seizure free with medical treatment. After 3 first-line antiepileptic drugs (AEDs) have failed, the chance for seizure freedom is 5–10%.

What part of the brain is damaged with epilepsy? ›

Seizures, particularly repetitive seizures, cause substantial brain damage in highly susceptible areas, such as parts of the hippocampus, entorhinal cortex, amygdala, thalamus and other limbic structures; however, neuronal death after seizures can be more widespread and is generally quite variable (e.g., [24, 77]).

What part of the brain is most affected by epilepsy? ›

The temporal lobes are the areas of the brain that most commonly give rise to seizures. The mesial portion (middle) of both temporal lobes is very important in epilepsy — it is frequently the source of seizures and can be prone to damage or scarring.

What part of the brain is affected in epilepsy seizure? ›

Epilepsy is associated with anatomical changes in the hippocampus, amygdala, frontal cortex, temporal cortex, and olfactory cortex. Knowledge of the anatomical basis of epilepsy will enable the understanding of the origin of the electrical activity, help accurate diagnosis, and guide appropriate management strategies.

Does temporal lobe epilepsy cause brain damage? ›

Over time, repeated temporal lobe seizures can cause the part of the brain that's responsible for learning and memory to shrink. This area of the brain is called the hippocampus. The loss of brain cells in the hippocampus may cause memory problems.

What triggers a temporal lobe seizure? ›

Temporal lobe epilepsy may be caused by an injury to the brain, such as a traumatic injury or infection. There are many other causes such as brain tumors, vascular malformations, and developmental abnormalities.

Can temporal lobe epilepsy cause changes in personality? ›

Temporal lobe epilepsy, like any form of epilepsy, may cause changes in your behavior and personality. The evidence for the drastic development of psychiatric conditions or alterations in behavior resulting from temporal lobe epilepsy is relatively limited and controversial.

What is the best medication for temporal lobe epilepsy? ›

For patients with MTLE, the most effective AEDs are those used to treat focal epilepsies such as carbamazepine, oxcarbazepine, levetiracetam, lamotrigine, and topiramate. [41] These agents can be monotherapy or, more often, in combination to achieve adequate seizure freedom.

What is the most serious type of epilepsy? ›

Tonic-clonic seizures, previously known as grand mal seizures, are the most dramatic type of epileptic seizure. They can cause an abrupt loss of consciousness and body stiffening, twitching and shaking. They sometimes cause loss of bladder control or biting of the tongue.

Can temporal lobe epilepsy cause dementia? ›

In this form of epilepsy, a high frequency of focal seizures gradually damages the hippocampal region of temporal lobe, leading to a significant memory loss. Synapse damage and synaptic protein loss are strongly related to the severity of dementia.

What are some interesting facts about temporal lobe epilepsy? ›

Temporal lobe epilepsy is the most common form of focal epilepsy. About 6 out of 10 people with focal epilepsy have temporal lobe epilepsy. Seizures in TLE start or involve in one or both temporal lobes in the brain.

What are the 4 types of epilepsy? ›

Tonic: Muscles in the body become stiff. Atonic: Muscles in the body relax. Myoclonic: Short jerking in parts of the body. Clonic: Periods of shaking or jerking parts on the body.

Can brain damage from seizures be reversed? ›

Most often it is not possible to reverse the damage caused to brain tissue by trauma but receiving prompt medical care may make it possible for medical providers to stabilize a person's brain injury and help to prevent further injury.

What drugs calm the amygdala? ›

Oxytocin reduces amygdala activity, increases social interactions and reduces anxiety-like behavior irrespective of NMDAR antagonism.

What happens if amygdala is removed? ›

Early primate studies have revealed that chemical and electrical stimulation of the amygdala region accentuates aggressive behavior. Conversely, destruction of the amygdala nucleus results in a taming effect of normal anger and fearing responses in primate behavior.

What happens when the amygdala is removed or severely damaged? ›

Understanding Damage to the Amygdala

The amygdala in particular controls the body's response to fear and emotional and behavioral regulation. When the amygdala sustains damage, it can cause difficulty with memory processing, emotional reactions, and decision-making.


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