April 21 2009

Carers and those who live day to day with schizophrenia have no doubts that it is an illness.
There has been a behaviour change - often one florid instance of abnormal behaviour, that cannot be explained in ordinary terms,
drawing attention to the recognition there has been an overall change in general behaviour, often wih a cognitive memory failure:
placing the person in a state of behaviour alien from previous competence, accompanied by withdrawal, by delusional misbeliefs, to their disadvantage,
which they are unable to reverse themselves to regain the previous state.

The illness continues on a course with the same pattern, as an autonomous living system, isolating the person from others, who cannot identify with the changed behaviour by using their own experience to understand it.

It is a mental illness, arising out of an adverse change in the function of the brain, the organ of the mind .

Unlike other medical illnesses the brain is removed from immediate access, without the risk of damage. There can be no biopsy , no test for a change at the time of the onset of the illness.
The diagnosis is made from observation only.

This has been the biggest challenge to accepting schizophrenia as a medical illness
That has changed since the ability to measure the changes in the brain, although at one step removed - by functional MRI - but standardising and verifying agreed conclusions from these studies has not yet arrived.

More persuasive evidence has come from brain material examined in post mortem tissue from those affected.Hippocampal new cell proliferation is halved in continuing schizophrenia
[Reif et al 2006
Allen et al:- 2015, replicated and confirmed

It is a common observation by family and clinicians that at the age at which schizophrenia starts that is where their lives remain.
At the age when schizophrenia arrives that is when the accumulation of further growing up experience stops.

The Evidence for this memory failure presented:-

From Clinical studies on whole catchment populations.
Two different field surveys of all patients in their community
Al usri et al : Kelly et al

They found a general memory failure in 80% of people with continuing schizophrenia.

From this sort of anecdotal observation in conversational meetings between patients and consultant psychiatrists E.G. ...

Just last week I saw a man in his 40's who is still pre-occupied with the pop singers of the early 1980's.'
Reduced working memory capacity did not allow this patient to add to his experience, from what was going on around him, thereby leaving his topics of conversational interest restricted to those which were his, before the age at which his illness started.

And a carer observes -
Evan, now aged 45, his schizophrenia illness starting in his late teens, his illness active as he kept stopping medication - till around thirty years of age, when he accepted continual depot medication since becoming now well adjusted with some residual vulnerability to schizophrenia symptoms, socially active and competent at his own pacing, skilled in photography, extremely competent in woodcraft, maintaining two or three gardens voluntarily , driving his own car, was noted by his family carer, to be in difficulty trying to read a Thomas Hardy novel, one that he had studied at school Asked to explain the difficulty he said ....'that what he read at the top of the page did not carry over to what he read at the bottom of the page{ See
He had difficulty in continuing to identify with the characters.
[ reading difficulty in schizophrenia ]
By practice, at a pace set by himself, his reading is improved. Fictional material remains difficult.
Two years later his memory seems to be improving, but seems to get out of context. The things remembered are correct, but not in the place that they happened. e.g Planting things at our last address rather than at another.
He also finds that any disturbance affects his ability to retain anything he has started out on.
Money is still a problem. i.e. budgeting. and some times seems to be in a cloud five.

From Academic research
Coras:- Brain 2010: 133; 3359 ....

What was known in rodents is now confirmed in humans. "A correspondence is found between the level of human hippocampal neurogenesis [ the ability to maintain continuous production of new cells ] and the level of effective working memory".
The researchers studied how stem cells in a memory-related region of the brain, called the hippocampus, proliferate and change into different types of nerve cells.
Scientists have been unsure of the significance of that process in humans.
Over the past two decades, several studies have shown that new nerve cells [ neurogenesis ] are continuously generated in the hippocampus.
In animal studies, disrupting nerve cell continuous generation resulted in the loss of memory function, whilst increasing the production of new nerve cells led to improved memory.

To investigate whether the same is true in humans, Coras et al , in collaboration with colleagues in Germany, studied 23 patients who had epilepsy and varying degrees of associated memory loss.
They analyzed stem cells from brain tissue removed during epilepsy surgery, and evaluated the patients' pre-surgery memory function.
In patients with low memory test scores, stem cells could not generate new nerve cells in laboratory cultures, but in patients with normal memory scores, stem cells were able to proliferate.

That showed, for the first time in human tissue a clear correlation between patient's memory and the ability of their stem cells to generatenew nerve cells.

from postmortem study.
Reif et al 2006[ now replicated and confirmed - Allen et al by Allen et al 2015 ]
Reif study was on post-mortem material from brain material ' stocked in bank ' much earlier.
The hippocampal area in tissue from schizophrenia is compared with that from mood disordered people and from normal controls.

In schizophrenia the hippocampus either is not carrying enough stem cells; or, it is not turning stem cells into enough new cells

Quote ..... " Does the finding of decreased Adult Neurogenesis [ AN ] in Schizophrenia make sense?"

" Sz is known to go along with several cognitive deficits, which is stable over time, that is, trait rather than state dependent.
The prime role of hippocampus is rather memory formation than affect regulation.
Thus, diminished Adult neurogenesis, which has been suggested to result in impaired memory formation, will contribute to the cognitive impairment seen in Sz;
As learning, exercise, and enriched environment all increase AN as well, this directly points toward non-pharmacological treatment of schizophrenics.
The preliminary finding of reduced AN in Sz provided in the present study is thus worth being pursued further." [ Ed !!!! ]

*** New !!!

Carbon dating !!! developed in the Karolinska in Sweden. They could verify Reif et al if they could acquire brain tissue from brains that sufferered schizophrenia.

Carbon14 hippocampus

A quite different way of measuring the state of neurogenesis in the dentate gyrus of the hippocampus has emerged.

These next three studies find what would be expected if hippocampal stem cell neurogenesis in schizophrenia was reduced
6.Gold et al
link to the Gold et al paper

Sufferers from persistent schizophrenia steadied on standard medication were asked to recognise and place colour worded items,
declaring them at one second and four seconds after exposure

What was examined was the number of items :-
accurately stored
retained to be able to show them at 4 secs.

" Patients show clear reductions in the number of items that can be stored in WM [ Ed Working Memory ] but no evidence that their WM representations are less precise or less stable than those of healthy individuals " Schizophrenia subjects were as accurate as controls, made no mistakes. But they did not store enough at first point.
The situation at delay showed no deterioration of capacity nor of precision.
Visual WM representations are neither less precise nor more prone to decay in schizophrenia.

Instead, patients exhibit a reduction in the number of items they can concurrently maintain in Working Memory

This next study also points to a remedy.
Raalten open access
in a sample of people with medicated schizophreniathe capability to profit from practice under stable learning conditions was unimpaired.
" When encouraged and accompanied, given the opportunity to practice,
sufferers do store what they have memorised: equally as well as for 'control subjects"

by 'chunking'.

Dutch researcher Tamar van Raalten investigated whether a disruption to the automation process, that is learning by repetition - to do something on automatic pilot, explains why people with schizophrenia can process less information. She established that it is not the 'automation' process but the processing of new information that failed.

Van Raalten first of all investigated the role of the working memory during 'automation'.

Van Raalten asked study subjects, positioned in an fMRI scanner, to perform tests in which they had to remember a series of letters. Working memory is then fully active. But the more the tests are repeated, less was the need for brain activity in the areas involved in working memory function. By automating the letter series, the study subjects therefore released working memory capacity so that normally it could once again process new information..

Van Raalten established that the decrease in activity was due to another function of the working memory; the restructuring of incoming information..

For example, you first of all remember a telephone number as a series of independent figures. But your working memory puts this series into 'chunks'. [ chunking ] Instead of 1-1-3-2-6-7-3-4-4-5, you remember 113-267-3445. ]
In this way you only have to remember three chunks and not ten individual numbers. This ensures that once a task has become fully automated after sufficient repetitive training, it can be performed without further involvement of the working memory. .
As a result of this it should be easier to do other things alongside the automated task..

Patients with schizophrenia process less information than healthy people. Their brains function less efficiently..

It was expected that less working memory in schizophrenia patients ensured that automation did not proceed well, as a result of which they could not release working memory capacity.
However, tests on schizophrenia patients revealed that after training, the brain activity decreased in the same manner as was the case for healthy study subjects. the automation of tasks proceeded without problems..

It might therefore be expected that schizophrenia patients would have the same released WM capacity to do a second task together the first, automated task. Yet in schizophrenia any released capacity of the working memory could not be used for a new task..

Following this 'surprise' result Van Raalten investigated where the problem could possibly be located..

During new tests she found that Working Memory in schizophrenia patients mainly struggled with the processing of information that continually changed.
{ This study now confirmed :- Koch et al
"... First evidence from studies with schizophrenia patients indicates that the potential to profit from short-term practice under stable learning conditions
( ie, when the same stimulus material is repeatedly being processed ) is largely preserved.
Patients showed significant performance improvements and significantly reduced WM activity with increasingly successful processing. ]
Where Evan - quoted above - could not remember at the bottom of the page what he had read at the top; that's a prospective memory task - trying to keep up with a forwarding fictional narrative requires holding a lot of background whilst moving forward ]
He had found the same with other books he had tried to read.

An experimental prospective challenge :-To test that also, prospective memory is affected in schizophrenia. [ Elvevaag et al: BMC Psychiatry 2003.3.0 ] research article open access ], based at NIMH and at the University of Warwick, compared the prospective memory of people with and without the disease.
In each test participants manoeuvred a ball around an obstacle course for 90 seconds.

The ongoing activity was a commercial battery-powered game ("Kongman"; TOMY Toy Corporation, 1982) in which a steel ball was to be moved around an obstacle course by pressing a button at the appropriate time points in order to open or close certain routes through which the ball could travel. Each game lasted 90 seconds, and participants were instructed to accumulate as many points as possible during each game until the time was up.

The Game commenced by each participant winding a timer at the base of the game. The game was sufficiently easy and enjoyable that participants engaged in the game and all participants performed extremely well.
[ i.e. the Study subjects with schizophrenia had rehearsed and so 'chunked' the game, and then did well on the basic test ... but then ...later ... ]

During the course of the game the timer moved from the start to the finish position ( taking 90 seconds ).
The rim surround of the timer was covered and colored with red and green colored paper, such that the first 25 seconds were red and the remaining 65 seconds green.

The Prospective Memory task was to turn a counter (a poker chip that was similar on both sides) over once during each game.
However, participants were instructed to turn the counter over only when the timer reached the green zone
(i.e., they could not respond prospectively immediately, but had to wait for some proportion of time into the game before responding).

were to play the game a total of 10 times (i.e., 10 trials). After each of the ten games, participants were asked if they had remembered to turn the counter over during the game. The experimenter employed a stopwatch to note the time at which the counter was turned over, and whether it was in the green or red zone. The participants' response to the question concerning whether they remembered to turn over the counter was also noted.

They were then asked [ the holding injunction ] to turn over a counter when they were at least 25 seconds into the test.

The time delay ensured that prospective [ i.e. recall for a future event ] memory had to be used.

Participants with schizophrenia were more likely to forget to turn over the counter.

At the end of the test the participants were asked if they had remembered to turn over the counter.

Approximately a third of the time participants with schizophrenia reported they had done so when they had not.

In summary:- In Schizophrenia, the hippocampus either is not carrying enough stem cells; or, it is not turning enough stem cells into new neurons, so as to support enough working memory

Links to study References

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