راهگاهی حسی، مصرف کانابیس و خطر ابتلا به روان پریشی

Sensorimotor gating, measured as the modification of eye blink startle reflexes to loud acoustic stimuli by quieter preceding stimuli, is altered in those with psychosis, their relatives and those at high clinical risk for psychosis. Alterations have also been shown in cannabis users, albeit to a lesser extent, and cannabis is a known risk factor for the onset of psychosis in clinically and genetically susceptible individuals. We examined the interaction between clinical risk for psychosis and cannabis use on sensorimotor gating, both Prepulse Inhibition (PPI) and Prepulse Facilitation (PPF). We tested PPI and PPF in participants with an At Risk Mental State (ARMS) for psychosis and a matched control group. Both groups included a proportion of subjects who had recently used cannabis, as confirmed by urinary drug screening (UDS) on the day of testing. We found that ARMS participants showed reduced PPF and PPI relative to controls, the latter driven by a group by cannabis use interaction, with recent use reducing PPI in ARMS participants but not in controls. When the analysis was limited to UDS-negative participants there was significantly reduced PPF in ARMS subjects relative to controls, but no differences in PPI. Within the ARMS group reduced sensorimotor gating, measured by both PPI and PPF, related to reduced overall level of function. Cannabis use in clinical high risk individuals may increase the risk of psychosis in part through worsening PPI, while PPF is altered in ARMS individuals irrespective of cannabis use. This develops our understanding of cognitive mechanisms leading to the experience of aberrant perceptual phenomena and the subsequent development of psychotic symptoms.

Sensorimotor gating is thought to play a role in how organisms allocate limited cognitive resources within a sensorially rich environment. Measuring the eyeblink startle reflex to a strong sensory stimulus, or ‘pulse’, can be used to study aspects of sensorimotor gating by examining the effect of a relatively weak preceding ‘prepulse’ (PP). This PP modifies the extent of the startle that follows according to the delay between stimuli, the inter-stimulus interval (ISI). When the ISI is short, between 30 and 480 ms, the startle reflex to the pulse that follows is attenuated, a phenomenon known as prepulse inhibition (PPI); with a longer ISI, between 500 and 2000 ms, the startle reflex to the following pulse is augmented, known as prepulse facilitation (PPF). PPI and PPF may reflect distinct processes: PPI at short ISI is thought to represent primarily an automatic pre-attentive gating mechanism (Braff et al., 1992), while attentional modulation of PPI occurs with ISI greater than 100 ms (Braff et al., 2001). PPF may represent later stages of sensory processing such as generalized alerting, orientation and passive attention (Graham, 1975). In patients with psychotic disorders, deficits in sensorimotor gating may lead to cognitive fragmentation disorganization and psychotic symptoms, but the stage at which processing is altered is unknown (Kapur, 2003). Deficits in PPI in subjects with schizophrenia are well established (reviewed in Braff et al., 2001), and have been related to cognitive impairments and positive psychotic symptoms (Kumari et al., 2008c), and have been correlated with reductions in dorsolateral prefrontal, middle frontal and orbital/medial prefrontal volume (Kumari et al., 2008b). PPI deficits have also been reported in people with schizotypal (Cadenhead et al., 2000 and Cadenhead, 2011) and psychosis-prone personality traits (Swerdlow et al., 1995a and Kumari et al., 2008a), and in the relatives of people with schizophrenia (Cadenhead et al., 2000 and Kumari et al., 2005). These data suggest that PPI deficits may be a marker of vulnerability for psychosis. There have been several previous studies of PPI in people at clinical high risk for psychosis. Quednow et al. (2008) found diminished PPI in this group, whereas Cadenhead (2011) found no differences between high risk subjects and controls, but increased PPI in high risk subjects who later developed psychosis relative to that in subjects who did not. More recently both Ziermans et al., 2011 and De Koning et al., 2014 found diminished PPI in clinical high risk groups, the latter screening out drug using participants using urinary testing. Biomarkers of clinical outcomes in this group are of particular interest, as they may facilitate the stratification of high risk samples according to the likelihood that an individual will subsequently develop psychosis or recover ( Fusar-poli et al., 2012). Studies of PPI in this group also have the advantage of being free of the potentially confounding effects of antipsychotic medication on PPI ( Kumari et al., 2007), as clinical high risk subjects are often medication naive. Although there have been several studies of PPI in relation to psychosis, there have been relatively few studies of PPF (reviewed in Kumari et al., 2004, Schiz Res, Appendix 1/2). Wynn et al. (2004) found reduced PPF in subjects with schizophrenia and their first degree relatives compared to controls. There have not been any studies of PPF in subjects at clinical high risk. A large proportion of patients with psychotic disorders and subjects at high risk of psychosis use psychoactive substances, particularly cannabis. Cannabis use can induce acute psychotic symptoms and is associated with an increased risk of developing a psychotic disorder (Arseneault et al., 2004 and Moore et al., 2007). Little is known of the effects of substance use on PPI or PPF in either clinical or healthy samples, and the importance of UDS screening is well known (Swerdlow et al., 1995b). One study found PPI deficits in cannabis-using healthy controls only in actively attended to trials (Kedzior and Martin-Iverson, 2006)—in these attentional modulation paradigms participants are instructed to actively attend to prepulse and pulse sounds, compared to passive attention designs where no such direction is given. Similar findings emerged from a later study that compared cannabis using and non-using subjects with schizophrenia alongside healthy controls (Scholes-Balog and Martin-Iverson, 2011). Administering cannabinoids during adolescence to mice reproduced PPI deficits and several other markers of schizophrenia, (Gleason et al., 2012) and these were reversed by antipsychotic treatment (Nagai et al., 2006). In the present study we set out to examine both PPI and PPF of the acoustic startle reflex in medication-free subjects with an At Risk Mental State for psychosis (Yung et al., 2005). They were compared with demographically- and geographically-matched healthy controls, and urinary drug screening was used to test for cannabis and other psychoactive substances. Our main hypothesis was that ARMS subjects would show PPI and PPF deficits relative to controls. A secondary hypothesis was that the findings would be modulated by cannabis use.

In this sample of subjects at high clinical risk for psychosis, we found deficits in both early and late stage sensorimotor gating, with the former moderated by cannabis use. Further work is needed to uncover the neural basis of sensory gating deficits and how these relate to aberrant salience and the development of psychotic symptoms.