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Abbreviations
DA
ERP
Dopamine
Event-related potential
F. Waters (*)
Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, and The University
of Western Australia, Private Mail Bag No 1, Claremont, Perth, WA 6910, Australia
e-mail: flavie.waters@health.wa.gov.au
185
R. Jardri et al. (eds.), The Neuroscience of Hallucinations,
DOI 10.1007/978-1-4614-4121-2_11, Springer Science+Business Media New York 2013
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F. Waters
fMRI
PFC
SZ
11.1
Introduction
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11.2
188
F. Waters
Early studies had reported conflicting results regarding the direction of error,
showing that individuals with SZ either overestimate time (Densen 1977; Johnson
and Petzel 1971; Wahl and Sieg 1980) or underestimate time (Johnson and Petzel
1971; Tysk 1990; Wahl and Sieg 1980). However, more recent studies involving
systematic comparisons of responding are largely consistent in showing that time
representation in SZ is better described as highly variable, without systematic
biases in either direction (Carroll et al. 2008, 2009; Elvevg et al. 2003, 2004; Lee
et al. 2009; Tracy et al. 1998). This is aligned with findings in general community
individuals, which show that time perception is subjective and highly variable, especially as the timing interval increases.
Altogether, these findings suggest that people with SZ show distortions and greater
timing imprecision when compared to healthy non-clinical control individuals.
Timing processes across long durations have typically been assessed using memory tasks where the temporal memory for events that occurred in the past is tested.
Often, memory of when actions were performed, or when items were presented, is
assessed. Tasks may require participants to make a recency judgment, indicate the
temporal position of a memory item, or classify items as a function of the test session in which they were presented. Studies of temporal memory show that people
with SZ perform less accurately than control participants (Dreher et al. 2001;
Elvevg et al. 2004; Rizzo et al. 1996; Schwartz et al. 1991; Waters et al. 2004),
even when the groups are matched on general memory abilities (Waters et al.
2004), providing evidence for the notion that long-term associative (or context)
memory involving a sense of time is impaired in this group.
A frequent criticism of the above tasks is the involvement of cognition other than
purely timing mechanisms. Difficulties in objectively measuring the internal clock
have led to a reliance on cognitive measures that involve a temporal component.
Thus, performance on such measures typically involves attention, working memory,
and memory processes (Lee et al. 2009; Ortuo et al. 2005; Shum et al. 2004; Tracy
et al. 1998), which are used to attend to the task, keep task instructions in mind, and
make response decisions. The concern is that performance deficits might be linked
to broader cognitive dysfunctions in SZ, rather than the internal clock. Thus, deficits
on timing tasks may be linked to difficulties performing the task rather on its timing
component. Many attempts have been made to control for cognitive involvement in
time-representation tasks (Elvevg et al. 2004; Waters et al. 2004), and findings
appear to suggest that timing processes are impaired irrespective of the level of
cognitive abilities. Nonetheless, other approaches have been used to circumvent
cognitive involvement when assessing time representation in SZ.
Time representation across short durations and/or with the use of preconscious measures. One method to avoid intervention from higher-order cognitive processes is to
use the fast and repetitive reproduction of simple movements (like finger tapping).
Some tasks require participants to tap in time to computer-generated tones, and then
to continue tapping at the same pace after the tones are discontinued. Studies show
that people with SZ demonstrate much variability on this type of task, and fail to keep
an even pace when compared to healthy control subjects (Carroll et al. 2009).
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11.2.1
Neuroimaging Findings
The above deficits demonstrated on behavioural tasks are supported by neuroimaging studies, which show that the brain systems normally supporting performance on
tasks of temporal representations (prefrontal and parietal cortices, thalamus, basal
ganglia, and cerebellum; Alexander et al. 2005; Harrington et al. 1998; Ivry and
Spencer 2004; Picton et al. 2006), are abnormally activated in SZ.
For instance, Volz et al. (2001) conducted a functional magnetic resonance
imaging (fMRI) study while volunteers underwent two tasks that required the discrimination of time and pitch (sound). Results showed that individuals with SZ
showed hypoactivity in the posterior putamen, anterior thalamus, and right medial
prefrontal cortex (PFC) that were related to timing performance. Ortuo et al.
(2005) also reported abnormal modulation of a corticalsubcortical network involving the supplementary motor area (SMA) in people with SZ during a timeestimation task. Finally, Ojeda et al. (2002) conducted a PET-015 water activation
study measuring relative cerebral blood flow during two counting tasks (counting
clicks, and then counting forward at the same rate after the clicks had stopped).
Results showed a differential pattern of performance depending on the task.
Counting clicks engaged more widespread brain regions in SZ than healthy controls, particularly in the inferior frontal regions. Counting forward unassisted,
however, yielded decreased activation in the frontal regions and inferior parietal
gyrus, suggesting that individuals with SZ failed to activate these regions at a similar level to controls during this task. Interestingly, behavioural performance was
not different from that of controls, suggesting that people with SZ may be using
different strategies in order to perform the task.
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11.2.2
F. Waters
Altogether, the above studies show that timing deficits are wide-ranging in SZ.
Deficits have been demonstrated using time-estimation methods and comparisontype tasks, and on tasks assessing short and long timing durations. Deficits were
also demonstrated in the auditory, visual and motor modalities, and at all stages of
information processing, ranging from preconscious to conscious processing. Using
Lewis and Mialls (2003) terminology, this points to impairments on both the automatic aspects of temporal processing (referring to repetitive or unconscious timing
tasks), and the resource-dependent controlled processes, referring to cognitively
mediated neural systems associated with attention and memory.
Altogether, evidence points to extensive timing abnormalities in SZ. But how
does this link to auditory hallucinations?
11.3
Few studies have directly investigated timing processes in individuals with auditory
hallucinations. However, timing is central to many neurobiological, cognitive, and
psychological explanations of these experiences.
Neurobiological models posit that dopamine (DA) abnormalities give rise to positive psychotic symptoms such as auditory hallucinations. It is posited that such
symptoms arise by increasing DA release in the mesolimbic pathway, as shown
from evidence that the administration of DA pharmacological agents in healthy
people produce symptoms of psychosis, and from findings of abnormal DA transmission in people with psychosis. This DA theory is relevant to timing processes,
given that DA manipulations can modulate timing perception by altering the speed
of the internal clock (Cheng et al. 2006; Macdonald and Meck 2005; Meck 1996).
For example, increasing brain DA levels with the administration of a DA agonist is
linked to an increase in clock speed, whereby DA antagonists decrease clock speed
(Meck 2005). Given that hallucinations are associated with DA abnormalities, and
that DA is linked to timing perception, one plausible suggestion is that hallucinations are mediated by timing deficits.
Cognitive and psychological explanations provide a different level of description by
detailing the mechanistic processes and functional significance of brain abnormalities for hallucinations. The importance of such models is that they are more closely
tied to conscious experiences than neural models. They can therefore provide explanations for complex subjective symptoms, and generate predictions that are testable
using scientific methods of enquiry. Theoretical models have identified several characteristic features associated with auditory hallucinations, including the failure to
self-recognition (perhaps linked to abnormal connectivity, self-monitoring deficits,
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11.3.1
Abnormal Connectivity
11.3.2
One motor-cognitive theory about auditory hallucinations suggests that a dysfunction of the forward-model system leads to difficulties in predicting the sensory consequences of ones intended actions and inner speech, and consequently a failure of
monitoring the origins of behaviours (self-monitoring) (Frith 1987; Frith 2005).
According to this model, incorrect sensorimotor predictions result in a failure to
recognise internally generated mental experiences so that they are perceived to have
a non-self origin. The importance of accurate timing for the forward-model system
and self-monitoring has been demonstrated in studies using self-produced tactile
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F. Waters
11.3.3
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11.3.4
Other theoretical models of auditory hallucination propose that neural activity, and
therefore mental experiences, are shaped by both sensory input and topdown attentional mechanisms (Frith and Dolan 1997; Krishnan et al. 2011; see also Chap. 6,
this volume). In this model, self-awareness is articulated as the product of sensory
input that is modulated by prior knowledge and attention. Topdown processes
modify sensory information in a way that is dependent upon ones expectancy and
prior knowledge.
This notion arises from the proposal that internal events are based upon hierarchically organised cortical systems, so that each level is influenced both by the input
provided by the level below, and expectations generated by the level above. This
system allows a distinction between ones own actions and intentions, and those
of agents in the outside world. The model posits a failure of this mechanism in
auditory hallucinations, so that the relative weighting between these two forces is
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F. Waters
11.3.5
Aberrant Salience
11.3.6
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195
the differentiation of one memory from another, a loss of such qualitative information
would make it difficult to infer the origins of mental events. These dysfunctions are
posited to lead to difficulties with self-recognition and decision-making about the
origins of mental events (Waters et al.2006a, b).
Theoretically, timing processes are pivotal for the functioning of cognitive functions. Brain functions (including thoughts, perceptions, and other cognitive events)
rely upon the coordinated interaction of a large number of neurons that are distributed across specialist areas of the brain. This integration of responding across different cortical regions is needed for the organisation of sensory, perceptual, and cognitive
systems. Such integration may occur either in parallel, or in sequential order, but
essentially requires fluid and dynamic adjustments depending on the nature of the
task. Abnormal timing processes would therefore have an impact on the orchestration of such sequencing ordering, and cause problems for the systems that support
cognitive functions and perceptual awareness. Specifically, timing problems might
result in a failure to adjust neural activity to the nature and demands of the task.
So, what would the functional consequence of timing problems on memory and
prefrontal functions for auditory hallucinations? Several consequences might occur.
First, the ability to represent the past, present, and future, and to integrate information across time, is a key function of the PFC (Fuster 1999). Thus timing impairments would impact on the ability to fully represent temporal contextual information
(as proposed above), as well as to plan future events, sequence behaviours across
time, and predict later events (still to be empirically tested). Second, the binding of
context cues in memory is reliant upon the frontal lobes and its connections with the
hippocampus and medial temporal system. Hence, a failure of integration would
lead to faulty integration of memory and executive functions into a composite memory trace, and difficulties forming an intact representation regarding the origins of
mental events.
Unsuccessful or less effective cognitive executive functions might also be
expected to increase auditory hallucinations through the lack of, or use of
non-effective, strategies for controlling unwanted intrusive thoughts, and by faulty
reasoning processes.
11.4
Conclusion
In this review, the mechanistic processes by which timing problems make a contribution to auditory hallucinations have been reviewed. Evidence suggests that these
problems might lead to difficulties in coordinating and synchronising internal systems that are responsible for perceptual analysis and cognitive functioning. Timing
problems are also linked to difficulties with forward-model processes and actionbinding. Finally, an abnormal sense of time may cause aberrant significance towards
neutral events. Altogether, time-keeping processes are fundamentally involved in
key phenomenological features associated with auditory hallucinations, notably
self-monitoring and misattribution.
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F. Waters
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