Neuroscience: week 2: Schizophrenia II
Mapping adolescent brain change reveals dynamic wave of accelerated grey matter loss in very early-onset schizophrenia
with the use of brain mapping algorithms, they detected striking anatomical profiles of accelerated grey matter loss in very early-onset schizophrenia
deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence
the earliest deficits were found in parietal brain regions, supporting visuospatial and associative thinking, where adult deficits are known to be mediated by environmental factors
over the course of 5 years, these deficits progressed anteriorly into temporal lobes engulfing sensorimotor and dorsolateral prefrontal cortices and frontal eye fields.
these emerging patterns corelated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search and frontal executive impairments in the disease
in temporal regions, grey matter loss was completely absent early in the disease but became pervasive later
only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies
the mapping strategy revealed a shifting pattern of tissue loss in schizophrenia
method of mapping strategy
three-dimensional maps of brain change were derived from high-resolution magnetic resonance images (MRI scans) acquired repeatedly from the same subjects over a 5-year time span
this procedure allowed us to pool maps of individual grey matter loss over time. Average rates of grey matter loss were computed for each group and compared across corresponding regions of cortex, before a more detailed analysis of nonlinear and age-dependent effects. The amount of loss and the rate of loss were separately evaluated.
Childhood-onset schizophrenia
this is a sever form of the disorder that appears to be clinically and neurobiologically continuous with the later onset illness
the cause is unknown, but increasingly suggested a neurodevelopment disorder
both early (pre-natal) and later abnormalities of brain development have been proposed, however, neither the anatomical pattern nor the timing of these developmental events has been established
in response to this, the brain mapping strategy is used to uncover deficit patterns as they emerged in populations imaged longitudinally through adolescence for 5 years
More about the mapping strategy
because grey matter loss in implicated in schizophrenia and is also known to occur in adolescence, we set out to create detailed spatio-temporal maps of these loss processes. Their timing and anatomical profile are fundamental to understanding how the disease emerges
in a recent cross-sectional genetic study based on a cohort of 80 adult twins discordant for schizophrenia, they isolated a genetic continuum in which cortical deficits were found in gradually increasing degrees, in individuals with increasing genetic affinity to a patient. By controlling for common genotype, we isolated discrete regions of cortex whose deficits were attributable to genetic and to nongenetic factors, although the emergence and timing of these deficits could not be evaluated
this cohort was followed for 5 years
this technique uncovered a dynamic wave of accelerated grey matter loss, spreading from parietal cortices at disease onset to encompass temporal and frontal regions later in the disease.
the rates and temporal sequencing of cortical grey matter loss was mapped in the teen years and was found to be greatly accelerated in diseased relative to healthy teens matched for age, gender and demographics.
the final profile was consistent with the loss pattern in adult schizophrenia. We also correlated loss rates with symptom severity and controlled for potential medication and IQ effects. This study is thus a three-dimensional visualisation of the timing, rates and anatomical distribution of brain structure changes in adolescents with Schizophrenia
this study suggests a dynamic structural basis for early prodromal symptoms and for the positive and negative deficit symptoms observed clinically
three dimensional cortical maps:
to compare and pool cortical data across subjects, a high-resolution surface model of the cortex was automatically extracted for each subject and time point. Based on the cortical models we created for each subject at different time points, a three-dimensional deformation vector field was computed that captured the shape change in the brain surface across the time interval. This method allows us to accommodate any brain shape changes when comparing cortical grey matter within a subject across time
to quantify local grey matter, they used a measure termed grey matter density, which measures the proportion of grey matter in a small region of fixed radius around each cortical point. given the large anatomic variability in some cortical regions, high-dimensional elastic matching of cortical patterns was used to associate measures of grey matter density from homologous cortical regions across subjects and across time.
annualised four-dimensional maps of grey matter loss rates within each subject were elastically realigned for averaging and comparison across diagnostic groups. Statistical maps were generated that indicated locally the degree to which grey matter loss rates were statistically linked with diagnosis, gender and positive or negative symptoms.
significance of the progressive loss:
schizophrenic subject underwent a significant, pervasive, and unrelenting loss of grey matter, with progressive deficits throughout superior frontal, motor and parietal brain regions and a separate loss pattern observed in temporal cortices. Normal adolescents also lost tissue even after normal variability was accounted for.
a subtraction map emphasised the loss pattern
regions of progressive loss, in both anterior frontal and temporal cortices, were anatomically circumscribed in both the percentage loss and significance maps and appeared to terminate anteriorly in the frontal eye fields.
the dynamic profiles of tissue loss suggests that a similar profile and degree of progressive grey matter loss may operate in schizophrenia, irrespective of gender
nonlinear loss
right parietal and sensorimotor cortices underwent significantly faster loss in the younger adolescents, consistent with recent findings of overall volume reductions specific to parietal lobes in younger patients.
In other brain regions, the rates of grey matter loss were not strongly affected by age, corroborating the use of annual averages to describe the dynamic pattern. Although nonlinear effects in other brain regions may be detectable in a much larger cohort, similar annual rates of loss were observed consistently in subject throughout our sample and across independent samples
Early deficits
Because of the apparent sparing of inferior frontal
cortices in the dynamic maps and their appearance
in the recent cross-sectional studies of adult schizophrenia, we were concerned that earlier (perinatal or prepubertal) nonprogressive maldevelopment may not have been observed in the dynamic maps, as these maps only capture loss that intensifies over time. To detect earlier loss, we compared grey matter profiles across all 24 is subjects at their first scan and at their last scan. Two features emerge
the severe progressive lateral temporal and dorsolateral prefrontal cortex deficit observes later was not apparent at 13, even at a mean of 3 years after the onset of psychotic symptoms. These symptoms were severely progressive after illness onset (average of 5% lateral temporal attrition per year) but were absent in the early phase of the disease.
secondly, the parietal and motor cortices showed a severe early deficit (up to 20% loss) with diffuse loss in other (but not temporal) cortical regions. This early (prepuberty) parietal deficit is consistent with the faster parietal loss found in younger patients, where as the dynamic loss in other regions is more uniform with age. The initial parietal deficit, which is also progressive, also occurs in regions where normal adolescents lose grey matter, although in disease this loss process is significantly accelerated. Although it is unclear whether the normal and aberrant processes have a similar mechanism or are independent, the parietal and motor cortical deficits are progressive and the earliest to develop.
it was recently also found that the parietal regions, are also in deficit in adult patients relative to controls, indicating that environmental and not purely genetic factors are implicated in triggering this deficit (at least in adults).
in the present study, a dynamic wave of progression from parietal cortices occurs later, into superior frontal, dorsolateral prefrontal and temporal cortices. These regions comprise a specific band of cortical territory in which adult deficits are thought to be strongly influenced by genetic factors as deficits here are found in unaffected relatives and significantly covary with an individual’s degree of genetic affinity to a patient. in our adolescent cohort, the temporal and dorsolateral prefrontal cortex deficits were among the most severe but began in late adolescence and were observed only after symptom onset
relationship to clinical deficits
the patient group deteriorated overall, whereas the average core for the IQ/medication control group remained stable. These findings suggests an overall deterioration of global functioning in Childhood-Onset schizophrenia, consistent with the progressive deterioration of structure.
at an individual level, rates of temporal loss correlated strongly with a SAPS total score at final scan. Faster loss in both the superior temporal gyri and the entire temporal cortices was significantly associated with a more severe clinical profile of positive symptoms (hallucinations or delusions). Although tissue loss rate were not significantly linked with the rate of change in SAPS scores from baseline and SAPS scores were not inked with the amount of tissue at baseline. loss rates were a good predictor of positive symptoms at a follow-up.
those with the least overall tissue deficit had the best cognitive performance in term of full-scale IQ at follow-up and those with the worst deficit on MRI had the lowest full-scale IQ at follow-up.
grey matter quantity as initial scan was also a good predictor of full-scale IQ in the patient group follow-up.
this linkage is consistent with the physiological hypothesis that negative symptoms of schizophrenia may depend on reduced dopaminergic activity in frontal cortices. The tight linkage between the deficit symptoms of schizophrenia and the pervasive loss of cortical tissue suggests a disease mechanism that may only be partially opposed by neuroleptics
Discussion
During the development of schizophrenia in these early adolescent subjects, a dynamic wave of grey matter loss occurred, starting in parietal association cortices and proceeding frontally to envelop dorsolateral prefrontal cortex and temporal cortices, including the superior temporal gyri. The deficits spread and intensified, in the same subjects, over 5 years of disease progression and eventually engulfed parietal, motor and supplementary motor, temporal (including primary auditory), and prefrontal cortices. The dynamic pattern is intriguing, as it begins in brain regions where deficits, at least in adults, appear to be mediated by environmental (nongenetic) factors (parietal cortices). It then progresses over a multiyear time frame into frontal and temporal regions where deficits appear, from our twin and other familial studies, to be strongly mediated by genetic factors
Relation to prior findings
The dynamic pattern of loss may also suggest a structural basis for the prodromal and chronic neuromotor, sensory, and associative deficits observed clinically and in studies of the functional and metabolic integrity of the cortex. Glucose metabolism is reduced in frontal cortices in chronic childhood and adult schizophrenics both at rest and during the performance of tasks that increase frontal lobe metabolism, such as The Continuous Performance Test. COS patients also display significantly increased metabolic rates in inferior frontal gyri, with marked decreases in superior and middle frontal gyri. This profile may mirror, to some degree, the discrete pattern of accelerated grey matter loss identified here. Whether or not this increased metabolism represents an adaptive or compensatory response to cell loss in superior frontal systems, a similar underlying patho-physiology may underlie these structural, metabolic, and functional impairments as the disease develops. The early parietal deficits observed here are consistent with recent functional MRI studies in adult patients showing marked
parietal activation deficits in working memory tasks. Recent functional imaging studies with positron emission tomography and functional MRI also show a diminished activation of the sensorimotor cortex and supplementary motor area during motor tasks (finger-to-thumb opposition) in schizophrenia. Implication of cortical motor systems is also consistent with premorbid motor impairments, consistently noted in studies of COS. In frontal cortices, regions of the fastest progressive grey matter loss terminated anteriorly in the frontal eye fields. Visual search tasks are throughout to tap a key attentional dysfunction in schizophrenia, namely a deficit in the ability to hone in on the most important elements in a picture and a tendency to stare instead of engaging in active visual search.
using exploratory eye movements during scene perception, impairments have been observed in schizophrenic adolescents in the basic control of exploratory eye movements, suggesting that they stared more and had difficulty in the top-down control of selective attention and visual search. Continuous attrition of grey matter in frontal eye fields may underlie some of the deficit symptoms in visual attention. The marked anterior limit of the loss pattern around the anterior limit of the frontal eye fields may indicate an anatomically specific progression that has a direct impact on the systems supporting attentional dysfunction.
recent neuropathological studies, specifically pathologic and in vivo MRI studies jointly, suggest that neuronal atrophy may be one anatomic substrate for deficient information processing in schizophrenia. Altered laminar density of cells in schizophrenic cortex and moderate reductions in cortical thickness may be major contributors to the intense dynamic processes of grey matter loss that are imaged here in vivo and mapped as they spread from parietal to frontal and temporal regions.
developmental implications
the research indicates that structural changes clearly progress after psychosis onset and well into adolescence, consistent with earlier reports of ventricular expansion and overall lobar reduction.
Cross-sectional studies of this COS population have also found a failure of normal maturation in neurological test performance during adolescence. This level of performance is also consistent with several recent brain structure studies showing more subtle but significant progressive cortical grey matter loss in adult-onset schizophrenia.
in this cohort, where parietal and frontal/motor deficits precede puberty, temporal deficits do not. it is probable that early neurodevelopmental abnormalities and later grey matter loss are related, as genes affecting prenatal development may also have roles in later brain maturation.
intriguingly (apparently) the earliest deficits occur in a region of parietal cortices where progressive cortical change occurs significantly in both healthy and schizophrenic subjects in the teen years.
in adults, parietal deficits appear to be mediated by environmental (nongenetic) factors, as the mathematical pattern of these deficits distinguishes schizophrenic adult twins from their healthy, genetically identical, monozygotic co-twins.
the frontal and temporal territories, which were spared when our cohort was first scanned, as later engulfed by the wave of tissue loss. In these regions, deficits in adult patients appear to be highly heritable. By dissociating early brain structure deficits that predate psychosis onset, those that progress, and those that begin in adolescence, dynamic and genetic brain mapping may shed light on the triggers of schizophrenia. These findings are consistent with the notion that activation of some nongenetic trigger contributes to the onset and initial progression of the illness.
Lecture:
specific genetic factor related to Sz; as its thought to have a hereditable component:
Copy Number Variant (CNV)
has been associated with schizophrenia and autistic spectrum disorder
CNV is on the 16p11.2 region of the 16th chromosome, which is associated with brain development- this part of the chromosome can be missing or duplicated, so we have a CNV
you have similar effects if that part is missing (depletion) or duplicated (duplication), included in diagnosis and similar problems in brain function, could also have no symptoms
how does this lead to brain differences such as dopamine?
not known but there are some genes related to dopamine within the CNV region
easier to link to more widespread brain differences though
difference between the brain of a healthy patient and of a schizophrenic patient
Sz patient has less grey matter
Sz patient has greater ventricle (the part in the centre of the brain that is involved in the flow of fluid throughout the brain)
hippocampi is more shrunk on Sz patient
temporal lobes degeneration in Sz patient
BUT brain pathology is already there when schizophrenia is diagnosed
Thompson, Paul M et al (2001)
they managed to get a cohort of young adolescence (about 12 yrs old) with early-onset symptoms of psychosis, they took MRIs of brain longitudinally, through out years
they scanned their brains, following the cohort through the early-on set of Sz, the magnetic imaging scans showed that there was severe loss of grey matter in parietal, motor, and temporal cortices (when looking at the image, red and pink areas reduced up to 5% annually)
how would this lead to symptoms?
it might be easier to link this general neuropathology to ‘underlying’, ‘basic’ cognitive symptoms, like memory, than hallucinations or delusions
cognitive differences in schizophrenia
Eye tracking in schizophrenia
those with Sz have a difficulty making smooth-pursuit movements with their eyes
a lack of smooth-pursuit indicates a cerebellum dysfunction/ damage, could be also linked to dopamine levels/ dopaminergic system,
prepulse inhibition
easily manipulated through dopaminergic systems/ levels
those with Sz can’t habituate the stimuli
a prepulse inhibition paradigm is habituation, the paradigm includes getting a pulse (like auditory through the ear), activates a startle response (prepulse) then getting a larger pulse (where you’ll probably be less startled due to the prepulse)
in Sz your prepulse inhibition is distorted
this can be linked to dopamine, and grey matter loss
Wisconsin card sorting task
this is a test of executive function, frontal cortex function
cards have different colours, shapes and diff numbers of shapes, they have to be organise in a certain way, like by colour, then the rule changes and you have to sort through this new rule, without reverting back to the first rule
those with Sz has subtle deficits like just carrying on with the first rule and may have difficulty to learn the initial rule
Theory of Mind in Sz
we measure this through the Sally and Anne task (healthy pps can do this by the age of 4/5), all about others’ perception and thought processes
ToM in schizophrenia
may find harder ToM tasks more difficult
their ability to do ToM tasks is not necessarily impaired or better than healthy pps, it is simply distorted
cognitive biases of Sz
cognitive biases- over report confrontational interactions
attentional biases- like anxiety over attend to negative stimuli (and those relevant to delusions)
reasoning bias- jumping to conclusions
interpretational biases- hearing voices
attributional biases
Seligman’s attributional model
3 dimensions: internal vs external, global vs specific, stable vs unstable
if negative events are interpreted as internal, global and stable this could lead to depression
the attributional style in psychosis would be external, global and stable potentially as this could lead to delusions
The family and broader social environment (nongenetic aspects of Sz)
The family in Schizophrenia
double bind and paradoxical communication
communication deviance
expressed emotion
mixed signals and emotional tones from mother growing up
SES and schizophrenia
socio-economic status
more household stress, triggering event,
lower access to support services, and educational facilities, more miscommunications within the family
poorer nutrition may affect brain development
social drift theory
those with Sz have difficulty with employment and drift to lower SES
sociogenic hypothesis
lower SES, more stressful life events
book states (Davey) that parental SES at time of birth is not associated with increased risk but there could be a nondirectional correlation, and this idea is controversial
how would you treat Sz as a psychologist?
social skills training
CBT like reattribution therapy
personal therapy
cognitive remediation training
family interventions- psychoeducation, supportive family management, applied family management
community care
LOOK AT DAVEY chapter 8