Background
Neuroimaging findings implicate bilateral superior temporal regions in the genesis of auditory–verbal hallucinations (AVH). This study aimed to investigate whether 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the bilateral temporo-parietal region would lead to increased effectiveness in the management of AVH, compared to left rTMS or placebo.
Methods
38 patients with schizophrenia (DSM-IV) and medication-resistant AVH were randomly assigned to 1 Hz rTMS treatment of the left temporo-parietal region, bilateral temporo-parietal regions, or placebo. Stimulation was conducted over 6 days, twice daily for 20 min, at 90% of the motor threshold. Effect measures included the Auditory Hallucination Rating Scale (AHRS), Positive and Negative Affect Scale (PANAS), and a score for hallucination severity obtained from the Positive and Negative Syndrome Scale (PANSS).
Results
All groups showed some improvement on the total AHRS. Hallucination frequency was significantly reduced in the left rTMS group only. The bilateral rTMS group demonstrated the most remarkable reduction in self-reported affective responsiveness to AVH. A modest, but significant decrease on the PANSS hallucination item was observed in the combined rTMS treatment group, whereas no change occurred in the placebo group. The left rTMS group showed a significant reduction on the general psychopathology subscale.
Conclusion
Compared to bilateral or sham stimulation, rTMS of the left temporo-parietal region appears most effective in reducing auditory hallucinations, and additionally may have an effect on general psychopathology. Placebo effects should however not be ruled out, since sham stimulation also led to improvement on a number of AVH parameters.
Auditory–verbal hallucinations (AVH) constitute one of the core symptoms of schizophrenia. Approximately 50 to 70% of all patients with schizophrenia report hearing ‘voices’ at some point during the course of the illness (Andreasen and Flaum, 1991). Furthermore, AVH persist in about 25% of cases, despite adequate treatment with antipsychotic agents (Shergill et al., 1998). Since the advent of neuroimaging techniques, there has been considerable interest in relating AVH to underlying brain structures and functions. Converging evidence from neuroimaging studies points to the involvement of speech production and perception areas in the genesis of AVH. Several structural neuroimaging studies have linked increased severity of AVH to volume reductions of temporal structures, particularly of the superior temporal gyrus (STG), mostly in the left hemisphere, but sometimes bilaterally (Onitsuka et al., 2004, Gaser et al., 2004 and Neckelmann et al., 2006). Functional neuroimaging studies furthermore suggest that in addition to secondary, and occasionally primary sensory cortices, abnormal activation in a distributed network of prefrontal, cingulate, limbic, subcortical and cerebellar regions appears to contribute to the experience of AVH (Shergill et al., 2000 and Lennox et al., 2000, and for a review, see Allen et al., 2008).
Transcranial magnetic stimulation (TMS) is a non-invasive technique that enables safe, relatively painless focal brain stimulation in humans. In repetitive TMS (rTMS) a train of pulses of the same intensity is delivered to a single brain area at a given frequency. Low frequencies (≤1 Hz) can suppress excitability of cortical neurons (Pascual-Leone et al., 2002). This observation suggests a therapeutic value against pathological neuronal hyperactivity observed in AVH (Hoffman and Cavus, 2002). Several studies have reported that application of low frequency rTMS over the left temporo-parietal cortex in patients suffering from AVH leads to an amelioration of symptoms, lasting for several weeks following treatment cessation (Poulet et al., 2005, Chibbaro et al., 2005, Hoffman et al., 2003, Hoffman et al., 2005, Lee et al., 2005 and d'Alfonso et al., 2002). In contrast, some experimental trials have yielded null effects or mixed results (Schonfeldt-Lecuona et al., 2004 and McIntosh et al., 2004). On closer inspection, methodological variables, such as the use of intermittent rather than continuous stimulation, may explain the absence of effect in these studies. Taken together results have generally been positive. This has been supported by two recently published meta-analyses that confirmed the superiority of rTMS over placebo treatment in reducing medication-resistant AVH (Aleman et al., 2007 and Freitas et al., 2009).
Most treatment studies of rTMS effects on hallucination symptoms have restricted stimulation to the left superior temporal area. However, evidence from neuroimaging studies point to potential bilateral temporal cortex involvement in the genesis of auditory hallucinations (Shergill et al., 2000, Lennox et al., 2000 and Lennox et al., 1999). The current study sought to investigate whether bilateral stimulation could improve the efficacy of the rTMS protocol, compared to left STG stimulation alone, and sham stimulation. Whereas left superior temporal areas are hypothesized to be involved in ‘speech’ perception during hallucinations, i.e. the comprehension of the phonological and semantic characteristics of the hallucinated content, right temporal cortex may be more associated with the processing of prosody and the emotional salience, as AVH are often derogatory and hostile in content. Accordingly, left STG stimulation seems most effective in treating relatively simple characteristics of AVH, such as frequency, loudness and attentional salience. We hypothesized that a bilateral treatment would contribute towards a more complete management of the symptoms, not only diminishing frequency of AVH, but also affecting emotional salience.
