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The legendary patient: H.M.

December 27, 2009

H.M. (Henry Gustav Molaison ;February 26, 1926 – December 2, 2008)

 This portrait of Henry Gustav Molaison, or H.M., was taken shortly before he underwent the experimental surgery that would destroy his ability to form long-term memories.

We knew him as H.M. from the beginning. He is by far the most important and famous patient in the neuroscience field.  You can find his initials in many neuroscience textbooks, and numerous articles.

What gave him this fame?

It was 1935. The Germans were not in Poland yet, and the World War II has not begun. It was an ordinary day in California and H.M. had an unfortunatebicycle accident at the age of nine. His tragedy started from that day; suffering from intractable epilepsy.  In 1953, HM was referred to William Scoville, a surgeon at Hartford Hospital, for treatment. This is how the most striking experience a human ever lived in neuroscience started. He got the operation for his epilepsy. On September 1, 1953, Scoville removed parts of HM’s MTL on both sides of his brain. HM lost approximately two-thirds of his hippocampus, parahippocampal gyrus, and amygdala. His hippocampus appeared entirely nonfunctional because the remaining 2 cm of hippocampal tissue appears atrophic and because the entire entorhinal cortex, which forms the major sensory input to the hippocampus, was destroyed. Some of his anterolateral temporal cortex was also destroyed (See the relevant entries Hippocampus: the seahorse that rides you and Amygdala: Yes, I love you and I remember you.)

He lost his short-term memory. His skill to take information and keep it as a long-term memory was gone with the epileptic tissues removed. The case was published in 1957, and his brain has been examined since then. There was nothing wrong with his ability to solve problems, he used to enjoy cross-word puzzles. He died at the age of 82, shedding light on the darkness on memory and teaching to the neuroscience community on the concept of memory through his sequelae after the epileptic surgical intervention.

Recently, his brain has been sectioned to be analyzed further at University of San Diego: in addition to the analysis done during his life by neuroimaging tools.  The slicing of his brain sample has been streamed on-line.

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Brain anatomy: tutorials from youtube

December 12, 2009

My picks as a neuroanatomist

 

3D MRI Human Brain Anatomy

 

Brain Anatomy and Functions

Human Anatomy – Brain

How the Body Works : The Regions of the Brain

How the Body Works : Center of Emotion and Memory

How the Body Works : Units of the Limbic System

 Anatomy of the Hypothalamus

The anatomy of autism

December 12, 2009

October is the Autism Awareness Month in Canada.

April is the Autism Awareness Month in U.S.A. and in England.

April 2 is the Autism World Awareness Day. Here is the website of Autism World Awareness Day.

What is autism?

Contrary to common belief, autism is the “umbrella term” for a list of disorders as it is the same thing for epilepsy.

Autism spectrum disorder (ASD) is a range of complex neurodevelopment disorders, characterized by social impairments, communication difficulties, and restricted, repetitive, and stereotyped patterns of behavior. ASD occurs in 1 in 150 children (Amaral et al 2008).

Autistic disorder, sometimes called autism or classical ASD, is the most severe form of ASD, while other conditions along the spectrum include a milder form known as Asperger syndrome, the rare condition called Rett syndrome, and childhood disintegrative disorder and pervasive developmental disorder not otherwise specified (usually referred to as PDD-NOS). Although ASD varies significantly in character and severity, it occurs in all ethnic and socioeconomic groups and affects every age group. Experts estimate that three to six children out of every 1,000 will have ASD. Males are four times more likely to have ASD than females.

Brain structures affected with most consistent findings

Structural MRI findings have been inconsistent to an extent, however, recently more solid information has been gathered on the brain structures which play role in the mechanism of autism. The brain is enlarged in autism (Mosconi et al 2006).

Postmortem and structural magnetic resonance imaging (see the structural MRI entry for more information) studies have highlighted the frontal lobes, amygdala and cerebellum as pathological in autism. However, there is no clear and consistent pathology that has emerged for autism. Moreover, recent studies emphasize that the time course of brain development rather than the final product is most disturbed in autism (Gordon 2007). It is believed that the patients with autism are not born with the changes in the brain, these changes appear through the development of the child in the first year of life (Mosconi et al 2006).

Cerebellum

Although cerebellum has been implicated as taking role in several neurological and psychiatric disorders such as in schizophrenia, temporal lobe epilepsy, bipolar disorder (see Cerebellum: Dark side of the moon entry for more information on cerebellum), the changes in cerebellum (e.g., cerebellar size) have reported more consistently and cerebellum is relatively more important in autism. It has been suggested that increase in the volume of the cerebellum might indicate abnormalities in the cerebellar–cerebral circuits that most probably result in the learning difficulties (Gordon 2007). Not only volumetric studies, but also functional studies also imply a developmental problem in the cerebellum in autism (Gowen & Miall 2007). In neuropathological studies (in post-mortem brains) decreases in cerebellar Purkinje cells and other changes have been reported in patients with autism (Palmen et al 2004).

Amygdala

Amygdala (see the entry on amygdala for more information about the structure) was reported as enlarged in children with autism. It has been suggested that amygdala enlargement was associated with more severe anxiety and worse social and communication skills (c.ref. Amaral et al 2008) such as a relation between nonverbal social impairment and amygdala volume was reported by Nacewicz et al (2006).

Frontal lobe

Both functional and anatomical abnormalities are seen in patients with ASD. These change in the frontal lobe are related to changes in cognitive performance such as reduction in the cognitive processing speed (Schmitz et al 2007).

Some other brain structures

Although cerebellum, amygdala and frontal lobe are the structures with most consistent findings in autism, other brain structures have also been found to be affected in autistic patients (Baron-Cohen 2004). Volume deficit found in parietal lobe of autistic patients was correlated with narrowed spatial focus of attention (c.ref. Baron-Cohen 2004). Hippocampus is another limbic system structure changes of which has been reported in autistic patients (Palmen et al 2004).

Decreases in the corpus callosum size; the white matter between the two hemispheres of the brain conveying information between these two hemispheres. Relations between several cognitive performance tests and size of corpus callosum were reported in patients with autism (Keary et al 2009). The changes in corpus callosum supports the fact that there might be a decrease in the connection between the two hemispheres (Hardan et al 2009).

Caudate nucleus; is a part of the basal ganglia. The structures of basal ganglia play a role in task we do where we do not need to remember to do them, like riding a bike or typing. We do them automatically once we learn how to do them. Parallel to the function of caudate nucleus, a relation between caudate nucleus and repetitive behaviors was reported in autistic patients (Rojas et al 2006; see the second reference in the suggested readings to reach the free full-text on-line). Enlarged caudate nucleus was found in high-functioning medication-free autistic patients which is a valuable finding, as the medication used for the treatment of autism affects the size of the caudate nuclei (plural for nucleus; Langen et al 2007).

Brainstem (related to sensorial information pathology in autism), thalamus, and anterior cingulate cortex, superior temporal gyrus are among the other brain structures of which changes were reported in autism.

Functional studies

Functional studies such as functional MRI , electrophysiological studies give us more information about the deficits in the brain networks. All these psychiatric disorders are now believed to be disorders with problems in the functioning of networks. A network is made by the several brain structures specific for a given task. A structure might belong to more than one network. Functional studies show problems in the functioning of some networks in autism. One of them is fronto-parietal systems/network specific for spatial (3-D) attention task. The pathways between cerebellum and cerebrum (the rest of the brain) contribute to this network. Although the role of cerebellum in attention in autistic patients has been questioned (Gowen & Miall 2007).

Suggested readings:

Understanding autism and related disorders: what has imaging taught us?

Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms.

A boy with Asperger’s syndrome prepares a video on his thoughts about his disease with his mom.

Do you know where to tickle my brain? Anatomy of laughter

December 11, 2009

george-costanza

There have been several ways to figure out which areas in the brain are responsible for certain tasks. Actually, we now know that one brain region just does not come along and get activated to make us do something, there is a circuit of structures working in a network of a given task.

Laughter is not an exception. When you read the stories of scientists discovering the “funny parts” of the brain, you realize how science/research can be an interesting journey.

A group of doctors from University of California were trying to explore a 16-year old girl’s brain who has severe epilepsy by using electric currents. They touched somewhere in the brain, and the girl started laughing. There were a bunch of guys in white coats surrounding her, and there was nothing funny around, even when looking at a picture of a horse made her laughing. The doctors, not the plan for that day, buzzed somewhere close to the speech centre (in the left frontal lobe), and did not need to make jokes to make their patient laugh. They concluded that speech and laughter centres are actually close, and that point they buzzed was a place in the network of laughter in the brain. More on that story, on circuit of laughter and an interesting story from early 1930s, about a guy who could not help laughing for a long period of time after showing up at the grave of his mother is here.

Actually lesions that exist in the brain give us ideas about the functions of the brain. In epilepsy seizures might rise from lesions. In the case where the patient has hypothalamic hamartomas that cause seizures, we observe the ictal laughter, where the patient is laughing during his seizure.

Epilepsy is an umbrella term for a long list of conditions with seizures. Gelastic seizures are a very rare form of epilepsy and the patients with gelastic seizures show this “ictal laughter” symptoms; recurrent bursts of laughter voices without mirth.

A case study (free on-line) on ictal laughter

Laughing consists of an affective and a motor component. It has been suggested that the affective component may result from an involvement of temporobasal structures, whereas the motor part is related to an involvement of the mesial frontal cortex. (The medial frontal lobe; also see “psychopathology of frontal lobe syndromes “;an informative page).

A 49-year-old woman with epilepsy had this laughter symptom originated from orbitofrontal cortex which is considered as a rare site of “ictal laughter”.

A 35-year-old woman with a lesion in the right supplementary sensorimotor area (SSMA) with epilepsy was investigated by stimulating the areas in her brain, and the researchers concluded that he anterior portion of the SSMA/lateral premotor cortex is involved in generating the motor pattern of laughter.

Pathological laughter is not seen only in epileptic patients but in other neurological disorders. It is also seen in patients with Alzheimer disease, and in patients with multiple sclerosis.

Here is a nice paper (free on-line) talking about the anatomy of humour:

Functional Anatomy of Humor: Positive Affect and Chronic Mental Illness

Katherine H. Taber, Ph.D., Maurice Redden, M.D., Robin A. Hurley, M.D.

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Increased hippocampal size after lithium treatment in bipolars

December 11, 2009

lithium

Q: What is bipolar disorder?

Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks.Bipolar disorder often develops in a person’s late teens or early adult years. At least half of all cases start before age 25. For more information please check the booklet on bipolar disorders prepared by National Institute of Mental Health.

Q: Why would a researcher be interested studying hippocampus in bipolar disorder?

Hippocampus has a role in cognitive proccesses such as memory, attention and emotional regulation dysfunctions of which are seen in patients with bipolar disorder.

Q: Is there a change in the size of hippocampus in bipolars?

No. Although researchers have found smaller hippocampi (plural for hippocampus) on both sides, left and right in patients with major depression, there is a tendency to believe that hippocampus size is similar to that of healthy normal controls in patients with bipolar disorder.On the other hand, with a relatively more sophisticated approach to structural analysis, three-dimensional mapping Bearden et al (2008) observed reduction in the subregions of the hippocampus in unmedicated bipolar patients, and they suggested a possible neural correlate for memory deficits frequently reported in this illness. Conventional structural MRI measurements might not be specific enough to detect any changes in hippocampal size in bipolars, compared to more sophisticated analysis detecting changes in a more detailed way at the subregional level.

Q: What is the treatment protocol for bipolar disorders?

Mood stabilizing medications are usually the first choice to treat bipolar disorder. In general, people with bipolar disorder continue treatment with mood stabilizers for years. Except for lithium, many of these medications are anti-convulsants. Anticonvulsant medications are usually used to treat seizures, but they also help control moods.

Atypical antipsychotic medications are sometimes used to treat symptoms of bipolar disorder.Antidepressant medications are sometimes used to treat symptoms of depression in bipolar disorder.

Lithium (sometimes known as Eskalith or Lithobid) was the fi rst mood-stabilizing medication approved by the U.S. Food and Drug Administration (FDA) in the 1970s for treatment of mania. It is often very effective in controlling symptoms of mania and preventing the recurrence of manic and depressive episodes.

Q: What was your approach in your hippocampal volume studies in bipolar disorder?

Most previous magnetic resonance imaging (MRI) studies of patients with bipolar disorder report similar hippocampus volumes across patients and controls, but because patients studied were heterogeneous with respect to course of illness variables and medication status, the conclusions of these studies remain equivocal. During my post-doctoral fellowship under the supervision of Dr.Glenda MacQueen who is now the head of Department of Psychiatry, University of Calgary we worked on a series of brains which have been collected since late 90s. This was a precious set, as there were patients who have started medication just only entrance to the study (unmedicated group), as well as patients who were medicated for a long period of time.

Q: What you have found in your studies about the size of hippocampus in patients with bipolar disorder?

We have used the structural MRI approach to investigate hippocampus in patients with bipolar disorder.

We have published our results in two papers; one showing short-term effects of lithium (1 to 8 weeks) on the hippocampal volumes of patients with bipolar disorder, another one showing the long-term effects (2 to 4 years). We did not find change in size of the hippocampi in patients who did not receive any type of medication in their lifetime or received for a very short period of time prior to their MRI scan (n=9) compared to those of healthy controls (n=30). We found increased hippocampal volume in patients who were on lithium (n=12) compared to those of controls. 12 patients who were on lithium were followed up for 2-4 years, and we also observed increase in the hippocampus size on both left and right sides.

Q: What are the clinical implications of your studies?

It is hard to come up with functional implications, as the cognitive performance of individuals are heterogeneous and not necessarily there would be a linear relationship between anatomy and function.

We,however, found preliminary evidence between increase in hippocampal size and improvement in verbal memory in bipolar patients.

Lithium might have a protective effect on a possible damage in the hippocampus as stated by a bulk of animal studies.

Q: What have the others found on the effects of lithium on the hippocampal size in patients with bipolar disorder?

Our studies were the first ones where we examined the effect of treatment with lithium on hippocampus size with a systematic approach.

Sax et al (1999) found no differences in hippocampal volumes between medicated and unmedicated patients with bipolar disorder.

No change in hippocampal volume was apparent in patients treated with lithium when compared to patients treated with medication other than lithium (Chen et al, 2004) or drug-free patients (Brambilla et al,2003).

Beyer et al (2004) found a correlation between Li use and an increase in hippocampal sizes in an older patient population.

Velakoulis et al (2006) found no change in hippocampal volumes of patients experiencing their first episode of mood-related psychosis; excluding those patients using lithium from the data did not change this pattern.

Foland et al (2008) reported increased volumes of the amygdala and hippocampus in bipolar patients treated with lithium compared with patients who were not taking lithium.

Bearden et al (2008) reported increased total hippocampal volume in lithium-treated bipolar patients compared with healthy controls and unmedicated bipolar patients.

An interview with me at Connections- St.Joseph’s Hamilton Healthcare’s NewsLetter

Cerebellum: Dark side of the moon

December 9, 2009

 TheDarkSideoftheMoon

If hippocampus is my love, cerebellum is my mistress. This has been my cliche since the last years of my PhD,  for almost 10 years. Again, just to explain how excited I am about cerebellum research, I come up with this anecdote. I am not a big fan of fyling (by plane I mean, as all the humans ever lived, I can not fly by myself.) When there is a tirbulance on the plane, I say “Oh, I must not die yet, I have not done research on cerebellum!”

       Why does cerebellum make me so excited? Cerebellum means “little brain” in Latin. Human cerebellum weighs 150 gr. which is 10% of the human brain. Our hippocampus important for short-term memory and emotional regulation only weighs 3-4 gr. Cerebellum is the biggest part of the brain. In spite of its big size, it has been a mystery over the centuries. Therefore I like calling the cerebellum “magic box or mysterious box”. When you take an average textbook; for medical students, for high school students; the first sentences you will see under the “Function of the cerebellum” subtitle would be how cerebellum is important in coordination, precision, and accurate timig of the movement. In other words, if you ask 10 people what comes to their mind when they hear the word cerebellum, 11 of them would say “balance.” The mystery under the brain (where cerebellum is located) is that cerebellum has functions not related to movements.  Following the advance in medical technology, particularly imaging (see functional MRI entry blog for an example) we have more evidence on that issue. The exciting part is we have a lot to learn about cerebellum’s role in psychiatric diseases.

Neuroscientists showed that cerebellum has a role in the mechanisms of psychiatric diseases such as in schizophrenia, attention deficit hyper-activity disorder, autism, and bipolar disorder.  Here is an article  from 2008 written as a review article by a Brasilian group titled as “Cerebellum with psychiatric disorders.” Another delicious article (that is how I call the papers I can not even read of enthusiasm) titled as “The Role of the Cerebellum in Schizophrenia: an Update of Clinical, Cognitive, and Functional Evidences” by a French group. Finally, here is an article on bipolar disorder and cerebellum where my dear friend ,who is also Turkish, Serap Monkul is the first author titled as “MRI Study of the Cerebellum in Young Bipolar Patients.” Serap also has spent time on doing structural MRI research in patients with mood disorders.

What is the deal with cerebellum having a part in psychiatry? Cerebellum has been suggested to take roles both in cognition, intellect, and emotions. It might be the fact that it can be not only the organ functioning for the balance of our movements, but also our psychological balance, as cerebellum is important in regulation of emotions.

  Suggested reading: “The role of the cerebellum in cognition and behavior: A selective review” from Helen Mayberg’s group (see famous brain researchers blog entry for information on Helen Mayberg).

          Finally, the title of the entry  is the title of  the last seminar I gave as a PhD candidate at Department of Anatomy eight years ago. It is also the title of one of my articles published in a Turkish journal; Journal of Neurological Sciences in 2002. Unfortunately, the link is broken for this paper, and the abstract was in English only,the journal now accepts articles in English, though.

Here is some more on cerebellum: The Treasure at the Bottom of the Brain

 

 

 

 

 

Hippocampus: The seahorse that rides you…

November 30, 2009

hippo

If it is  a morning, and I am looking for one of my favourite ties just after shaving, I might probably be leaving the house soon to give a presentation, and most likely it would be on hippocampus. For the last nine years (my first presentation on hippocampus dates to 24 January 2001) I gave at least dozen presentations to different types of audience on hippocampus. It is not a big surprise when you think I have been doing research hippocampus all that time.  My guess is hippocampus will take its role before my eyes while me watching the movie of my life when dying. Therefore, it would be so easy to write this post. Was it so? I have been neglecting writing this post for three weeks. Now, I have decided, if I am this hippocampus researcher, how would I tell this to “me” 20 years ago who had no idea about hippocampus. Let’s go! Listen Kaan who is only 19 years old (poor guy!)…This is the story of your future!

Here I am 17-18 years old, a high-school student, so this is the guy I am talking about/to…

 

 

 

Hippocampus, by far, has been the most famous brain structure , particularly for the last two decades, thanks to the advance in medical research technology. It is in the medial temporal lobe like amygdala . If you remember, or read that post now, temporal meant “time” in Latin. Of course the Latin people did not know anything about this part of the brain that time. The bone was named so, and centuries later the part of the brain lying on it. The part of the hair starts getting grey on the temporal bone, that is why it is called the “time”. Interestingly, the structures in it are related to the time. Hippocampus is the main brain structure responsible for short-term memory. If you give your phone number to someone, and ask him or her to repeat you after a minute, he or she can. Because his or her hippocampus is functioning. Alzheimer patients eat dinner, and they ask “when is the dinner?”. Because their hippocampi (plural for hippocampus in Latin) are not functioning properly. So the information is taken and thrown to the long-term memory (we do not know a lot about the processes related to the long-term memory) in the hippocampus. If you think, hippocampus is also related to the modulation of emotions, it would not be a shock when I say hippocampus is the star of psychiatry research.

   Giulio Cesare Aranzi  an Italian anatomist from Bologna first used the term hippocampus for the structure in 1564. He named the structure hippocampus as it looked like a seahorse. 

  Ancient Greek  (hippos; horse, seahorse, campos; seamonster)

Hippocampus is  2-inch (5 cm) in length. Its volume has been measured in many psychiatric and neurological diseases on magnetic resonance imaging (MRI; see the structural MRI post , please if you are curious how).

There are almost 20 disorders where people reported smaller hippocampal volumes compared to those of the healthy controls.

 Most popular ones are:

Alzheimer’s disease

Epilepsy (temporal lobe epilepsy)

Schizophrenia

Major depressive disorder

Post-traumatic stress disorder

       I am going to talk about hippocampus and bipolar disorder after the next post. So let me finish this one, with the list of factors related to smaller hippocampal size in patients with major depressive disorder ( I have done research on mood disorders @ University of  California San Francisco for 1.5 years,  @ McMaster University, Canada for 4 years)

1) anxiety

2) history of childhood abuse

 3) long illness duration

4) being untreated

5) serotonin genotype

6) clinical outcome

 7) resistance to treatment

Do not forget!  Scientists all over the world are trying to review and update this list with their extensive and valuable research.