This study builds on previous research which has investigated the awareness of agency in schizophrenia patients with and without delusions of control. Individuals suffering from schizophrenia can show delusions which cause them to believe that their thoughts and actions are in control of external forces. In such individuals, previous research has shown that there is increased and abnormal activity in certain brain areas when compared to healthy subjects. This fMRI study therefore investigates how these brain areas respond in two different tasks: 1) awareness of action discrepancy, and 2) awareness of action authorship. An experimental paradigm used by Farrer et al (2007) will be replicated, using a manual peg removal task. It is expected that in healthy individuals and schizophrenics without delusions of control will show normal activity in the specified brain areas in both of the studies. However, schizophrenics with delusions of control will show abnormally high activity in both studies, demonstrating an abnormality in brain function.
Scientific Summary (max 200 words):
Currently, there is a wealth of research investigating action authorship in healthy individuals and schizophrenics. These have shown that the rIPL, specifically the Ag, and the TPJ in healthy subjects and schizophrenics without delusions of control show increased BOLD signals to the experience of agency (self or other). However, it has been found that schizophrenics with delusions of control exhibit hyperactivity in these areas, and are more likely to misattribute an action to themselves or an external force. An experimental paradigm used by Farrer et al (2007) will be replicated, using a manual peg removal task – as research is somewhat ambiguous when it comes to brain activity relating to awareness of action discrepancy and awareness of action authorship, the two will be separated into two studies. It is expected that in both studies healthy subjects and schizophrenics without delusions of control will show normal brain function – rIPL activity to detecting a delay in the first study, and TPJ activity to the experience of agency uncertainty. However, the schizophrenics with delusions of control in study 1, will show hyperactivity of the rIPL and TPJ BOLD signals due to their perceived ambiguity of action agency, and study 2, will show similar results as they misattribute the action to external forces more so than the other subjects.
1. Background of the Project:
Distinguishing oneself from others is something we all take for granted and give the self-other distinction and the source of our perceptions very little explicit thought in everyday life. It seems that the self-other distinction is automatic and operates via non-conscious cognitive processes and aids us in daily social interactions and situations (van den Bos & Jeannerod, 2002). However, this ability is not clear-cut and definite in all individuals as it can be impaired to varying extents in a range of pathological and psychiatric disorders, i.e. schizophrenia.
Schizophrenia is characterised by irregular beliefs, behaviours and experiences. Additionally, patients can typically exhibit symptoms which indicate abnormalities in self-attributing their own actions and thoughts: symptoms such as acoustic or verbal hallucinations and delusions of alien control can all relate to a sense of losing authorship/agency and giving the feeling of being controlled by external forces (Mellor, 1970; Spence et al, 1997). Schneider (1995) classed these as the first-rank symptoms and these were explained by the individuals losing their normal capability to monitor their self-generated intentions and actions (Feinberg, 1978; Frith, 1992).
Before considering where these deficits lie in schizophrenia individuals, it is important to establish how the brain areas of healthy subjects function in response to agency tasks.
Functional neuroimaging has allowed the neural correlates of motor control to be examined in great detail. In healthy subjects, awareness of action has been associated with the right inferior parietal lobule (rIPL) (Frith et al, 2000; Sirgu et al, 2004). Additionally, increased activity has been reported in specifically the right angular gyrus (Ag) of the rIPL when healthy subjects show an awareness that they are not in control of a certain motor action (Farrer & Frith, 2002; Farrer et al, 2007). Further evidence has found that the Ag activity is correlated with the degree of discrepancy between the intended consequence of the action and the actual consequence of the action (Farrer et al, 2003). Other neuroimaging research has demonstrated that when healthy subjects do not feel authorship of an action or when they sensed a discrepancy between predicted and actual movements, activity in the temporo-parietal junction (TPJ) was increased (Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). This suggests that the TPJ has a very important role in whether we feel a sense of authorship of an action or if there is a discrepancy present.
The first model which accounts for the mechanisms underlying the sense of agency is the Predictive Forward Model of motor control (Wolpert et al, 1995; Frith et al, 2000; Haggard, 2005). This model states that when an action is performed, predictions are made about the sensory movement consequences; this is based on the motor efference copy (von Holst & Mittelstaedt, 1950). Next, such predictions are compared with real sensory feedback signals which arise as a consequence of the
movement and these contribute to a sense of agency if no error signals are arise. If the comparison fails, and error signals occur, then the action is experienced as other-generated, or as action failure which can be corrected without conscious awareness (Slachesky et al, 2001).
Now, considering schizophrenia individuals, delusions of control can comprise the belief that one’s actions are being influenced by an external force/agent (e.g. an alien, spirit or machine) (Mellor, 1970). When patients with such delusions are compared to schizophrenics without delusions of control they show impaired motor performance (Mlakar et al,, 1994; Spence et al, 1997). Recently, neuroimaging studies have allowed motor control and any dysfunctions in the neural correlates to be investigated. Firstly, research has shown that like healthy subjects, schizophrenic patients show increased activity in the rIPL when looking at action authorship; however, a different pattern is seen. The spontaneous resting activity of the rIPL is significantly higher than that of healthy subjects (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011) and additionally, this activity is poorly modulated by a discrepancy between predicted movement and actual movement consequences (Farrer et al, 2004). This would suggest that there is a deficit in the parietal mechanism which could be responsible for the impaired sense of agency found in schizophrenia. In relation to the TPJ, there have been anatomo-functional changes which have been reported in schizophrenia (Torrey, 2007; Wible et al, 2009), and sulcal displacements and volume reductions in this region were evidenced in patients who reported delusions of control (Maruff et al, 2005; Plaze et al, 2011).
Previous studies have not been able to disambiguate between brain activity related to awareness of action discrepancy and awareness of action authorship in schizophrenic patients. Therefore, the present study is going to use a slight modification of Farrer et al (2007) experimental paradigm in order to clarify which brain areas are functioning or functioning abnormally in response to the task. It is unclear specifically which process recruits which aforementioned brain regions and this can be achieved by using an experimental design which breaks down the processes into two separate methods. Two fMRI studies will be undertaken and manipulations will include: 1) the awareness of one’s own action being consistent with the predicted action and 2) the experience of being the agent or not being the agent of an action (i.e. authorship/agency).
Study 1 will include delays in visual feedback of actions to manipulate the relationship between predicted and actual sensory consequences of the action. Therefore, brain activity can be monitored to see when subjects are aware vs. unaware of these discrepancies with no bearing on authorship. Uncertainty of authorship will be introduced in study 2 to allow the observation of brain activity in response to manipulations of action authorship.
2. Questions to be answered:
Will a difference be found in rIPL and TPJ activity of healthy subjects, schizophrenics with delusions of control and schizophrenics without delusions of control in study 1?
Will a difference be found in rIPL and TPJ activity of healthy subjects, schizophrenics with delusions of control and schizophrenics without delusions of control in study 2?
Will there a difference in brain activity between studies 1 and 2?
3. Plan of Investigation:
In accordance with medical research guidelines, after complete description of the study, written informed consent will be obtained from each participant. 12 schizophrenics with delusions of control (6 male, 6 female), and 12 schizophrenics without delusions of control (6 male, 6 female) will be recruited from London teaching hospitals, satisfying the DSM IV-R criteria for schizophrenia. Additionally, 12 healthy subjects (6 male, 6 female) will be used as controls, matched on age, sex and IQ. Each participant will be identified as right hand dominant.
A quantitative assessment of the schizophrenia symptoms will be performed using the PANSS (Kay et al, 1987). Criteria for the schizophrenic patients with delusions of control are that they score 4 or 5 on the “delusions of control” item in the Scale for Assessment of Positive Symptoms (Andreasen, 1984). The criteria for the schizophrenics without delusions of control will be that they have never experienced such delusions.
Exclusion criteria will include any history of substance abuse or dependency, as well as any history of serious head injury or any other neurological or psychiatric disorders.
3.2. Stimuli & Procedure
As stated before, the experimental paradigm is very similar to Farrer et al (2007).
Study 1: A manual peg task will be performed with visual feedback delayed by 0, 50, 100, 150, 200, 300 or 300 ms. A board with 33 holes and 25 pegs will be used. For each experimental block the placement of the pegs will be different to avoid any recall of peg positioning. An infrared camera will film the grid and this image will be sent to a delay unit and be delayed for the required time. The feedback image will then be linked to the LCD projector so that the subjects are able to see the delayed action feedback on the rear projection screen at the head of the bore.
Therefore there are 7 conditions: 1 with no delay, and 6 with varying delays. A block design will be used with 8 blocks (20s each); the subjects will have to remove the pegs from the board for the 20s duration – this will then be followed by a rest condition with no action required or stimuli present. Each run involved the 7 conditions in a counterbalanced order. After each block finishes, each subject will be asked to state whether they perceived delays in the visual feedback of their movements: the right hand thumb down for “no” and thumb up for “yes”.
Study 2: The procedure and stimuli will be the same as study 1. However, the subjects will be required to perform index and middle finger alternating actions without pause whilst watching the feedback screen. The delays used will be 800 and 1000ms. Each run will consist of 120s of alternating finger movement, and 30s rest and will be repeated 5 times. The subjects will be told that they can either see their own or another’s movements after the delay, and this would occur randomly. However, in fact subjects will only be able to see their own movements delayed, causing them to switch from self to other. They also will be required to assert whether they think they see themselves or another individual carrying out the action. They will be required to press one of two buttons to show this. To prevent any other source of recognisable information that could give away the authorship of the movement, subjects will be required to wear a snug fitting glove to prevent any recognition cues.
3.3. Image Acquisition and Analysis
Studies 1 and 2 used the same functional imaging acquisition procedure. A 1.5-Tesla MRI scanner with a SENSE head coil will be used. For each run an ultrafast echo planar gradient echo imaging (EPI) sequence sensitive to blood oxygenation level-dependent (BOLD) contrast will be used to obtain 25 slices per time repetition, (4.5mm thickness, 1mm gap, in plane resolution, 3.125 x 3.125mm). TR = 2500ms, TE = 35ms. A co-planar, T1-weighted, axial fast spin echo sequence will be used to acquire 25 slices (4.5mm slice thickness with 1mm gap), TE = Min full, TR = 650ms, ET = 2, field of view = 24cm. A whole brain T1-weighted structural image will also be acquired (0.94?0.94?1.2mm) (Farrer et al, 2007). A head restraint will also be used to reduce any head movement during the scan in order to reduce any motion artefact.
4. Details of Data Analysis:
Both studies 1 and 2 will perform image analyses and statistical analyses using the SPM99 (http://fil.ion.ucl.ac.uk/spm/software/spm99). Functional scans will be realigned, spatially normalised and smoothed using a Gaussian kernel to remove any movement artefacts and to place the data from each subject into a common anatomical frame. The statistical analysis is similar to the analysis carried out by (Farrer et al, 2007).
Study 1: Two statistical analyses of the fMRI data will be performed. Firstly, movement-related activity, a simple contrast between the experimental blocks and the rest blocks. Secondly, delay-detection activity, the subjects’ responses in the detection of the delay will allow the assessment of between trials where subjects did or did not perceived the delay (Farrer et al, 2007).
Study 2: Two statistical comparisons will be performed. Firstly, movement-related activity, the experimental blocks across all conditions for each subject will be grouped and the main effect of task will be created. Secondly, perturbed agency, the subjects’ response to the visual feedback will allow differentiation between trials where the subject experienced self or other action authorship. (Farrer et al, 2007).
For both studies, one-tailed t-tests will be used for each of the contrast images. The set of t-values obtained will constitute a statistical parametric map which will show significant areas of BOLD signals.
5. Expected Outcomes:
The Expected fMRI Results:
Study 1: Consistent with prior research, it is expected that the healthy subjects will show significant activation in the in the rIPL, specifically the Ag, when detecting a discrepancy (detection of delay) (Frith et al, 2000; Sirgu et al, 2004; Farrer & Frith, 2002; Farrer et al, 2007). No TPJ activity is expected in the healthy subjects as study 1 is not meant to bring about the experience of agency uncertainty; this will be supported by previous research which shows the TPJ to have a role in determining if an action is not ours (Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). Schizophrenics without delusions of control are predicted to show very similar brain activation to the healthy subjects; this can be justified because they have had no prior experience of delusions of control and shouldn’t have any problems with determining action authorship (Spence et al, 1997) – however, this is not entirely certain, and only a prediction. As for the schizophrenics with delusions of control, it is expected that brain activity will be abnormal; the delay detected by the patient could elicit hyperactivation in the rIPL, specifically the Ag,
and the TPJ and give rise to misattribution of agency (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011). Unlike the healthy controls and schizophrenics without delusions of controls, it is predicted that they will be unable to attribute the movement to themselves after the delay.
It is expected that because of the ambiguity of the movement in terms of agency, healthy subjects and schizophrenics without delusions of control will show increased activity in the rIPL, but also in the TPJ due to the uncertainty of agency (Frith et al, 2000; Sirgu et al, 2004; Farrer & Frith, 2002; Farrer et al, 2007; Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). After being told that the action is ambiguous (i.e. self or other) it is predicted that the schizophrenics with delusions of control – similar to study 1 – will be more likely to misattribute the movement to another agent with a greater perturbation of their sense of agency compared to the other subjects. Additionally, the activity in the rIPL and TPJ is expected to show hyperactivation in comparison to the other subjects. (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011). Finally, it is expected that there will be a greater overlap between brain areas active in both studies for the schizophrenics with delusions of control compared to the other subjects.
6. Details of any difficulties that can be foreseen:
Although the subjects will be paid for their participation in the study, locating both schizophrenics with and without delusions of control may prove to difficult as they must be situated near the fMRI site as it is very unlikely that they will wish to travel long distances due to time and other issues. The criteria provided will narrow down the potential sample further.
When using fMRI, it is important to acknowledge that the BOLD signals are considered to be an indirect measure of brain activity, therefore potentially, all brain responses may not be recorded for each of the stimuli. However, fMRI is viewed as one of the most effective ways to investigate brain activity without invasive procedure in this paradigm. It will be made certain that all precautions are met, and imaging acquisition and analysis are meticulously carried out.
Due to the nature of schizophrenia and the wide variety of symptoms shown, it is possible that during the scanning process, certain subjects might experience symptoms that are debilitating to the scanning process which are out of the control of the experimenter. Medical staff will be on standby in case any violent/aggressive symptoms occur. There is a small chance of such an incident happening, but careful preparation can minimise the risk.
7. Future purpose and Theoretical Implications:
If the results are as expected, this will have significant implications for several research areas. Firstly, it will add to the abundance of literature on the involvement of the rIPL and TPJ in response to action discrepancy and authorship in healthy individuals (e.g. (Frith et al, 2000; Sirgu et al, 2004; Farrer & Frith, 2002; Farrer et al, 2007; Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). Furthermore, it will demonstrate that symptoms vary massively across schizophrenia patients – there are deficits in the functioning of neural correlates (i.e. the rIPL and TPJ) between those with and without delusions of control, and will add to the relevant literature (e.g. (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011).
Future research could delve into the severity of the symptoms of both the schizophrenics with and without delusions of control, and investigate whether it has an effect on subsequent brain activity. If a significant correlation is found it could be used as a “state-marker” of schizophrenia. As Jardri et al (2011) suggested such an increase in activity of the rIPL and TPJ in those with delusions could demonstrate a neuro-physiological signature in those suffering from the disease.
Additionally, it gives further evidence that the deficient parietal mechanism is responsible for the impaired sense of agency demonstrated in schizophrenics with delusions of control. Therefore, as they have problems linking their intentions to their actions, it suggests that for future research the disconnection should not be looked for at the sensorimotor level, but rather, like this experiment, it should be looked for within the cortical network which is known to be responsible for the representations of motor function.
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