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Keywords:

  • heart rate variability;
  • repetitive transcranial magnetic stimulation;
  • schizophrenia

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Repetitive transcranial magnetic stimulation (rTMS) has been reported to be an effective treatment for auditory hallucination (AH) in schizophrenia patients. The efficacy of rTMS and immediate changes in cardiac autonomic function (CAF) after rTMS in severe schizophrenia patients with AH (n = 8) were investigated. Three patients reported a ≥50% reduction of AH after rTMS. The ratio of low-frequency power to high-frequency power, an index of sympathetic modulation, increased significantly after rTMS. Further replication studies with larger sample sizes are indicated.

AUDITORY HALLUCINATION (AH) occurs in 60–70% of schizophrenia patients, and 25–30% of patients with AH are refractory to antipsychotic drugs.1 Repetitive transcranial magnetic stimulation (rTMS) has been proposed as an effective, well-tolerated treatment for psychiatric disorders, and it causes neither major complications nor neurocognitive impairment.2 A series of studies conducted by Hoffman et al. showed reduction of AH in schizophrenia patients after 1-Hz rTMS.3,4

Electroconvulsive therapy (ECT) had been approved to be effective for schizophrenia patients. With regards to cardiac autonomic function (CAF), the electric shocks administered in ECT have been reported to escalate sympathetic modulation and suppress vagal control.5 The influence on CAF by rTMS, however, is still unclear.

Frequency-domain analysis of heart rate variability (HRV) is a specific and time-saving tool for analyzing CAF. HRV is categorized into high-frequency power (HF) and low-frequency power (LF) components: HF is considered to be an index of vagal activity, and the ratio of LF to HF (LF/HF) is considered to reflect sympathetic modulation.6 In the current study, the efficacy of rTMS for AH was evaluated. Also, the effects of rTMS on CAF were assessed using HRV.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Participants

In the present study we recruited chronic schizophrenia inpatients who were diagnosed on DSM-IV criteria and who had been treated with antipsychotics in the therapeutic range for >2 years but who still had active AH. Patients who were willing to try rTMS reported their past history (i.e. seizure or convulsion, brain surgery or injury, stroke, metal implant in the brain, pacemaker . . . etc.) to exclude those who had contraindications for rTMS.7 We then explained the study in detail to suitable patients, and they gave their written informed consent before entry. This study was reviewed and approved by Yuli Veterans Hospital Review Board (YLVH-IRB no. 95-05-02-A). Nine patients were recruited into the study but one dropped out due to exacerbation of AH. The demographic characteristics of the eight patients who completed the study were as follows: male : female, 7:1; age (mean ± SD), 41.6 ± 5.0 years (range, 34–48 years), duration of illness (mean ± SD), 21.3 ± 4.5 years.

Protocol of rTMS

Patients lay on an examination bed and received 1-Hz, 90% of the motor threshold, 16-min rTMS over the left temporoparietal cortex between 14.00 and 15.00 hours in daily sessions for 11 days. There were two basic components of rTMS: lying down for 16 min and magnetic stimulation. We therefore designed sham stimulation to control the effects of lying down. On day 3 and day 9, sham stimulation was administered instead of active stimulation, but patients remained blind to this.

Collection of electrocardiogram signals and frequency-domain analysis of HRV

From day 1 onwards, a precardial 5-min electrocardiogram (ECG) was recorded before and after rTMS and the raw ECG signals were analyzed using a computer program with a modification of our previous method,8 according to the guidelines of the American Heart Association.6

Clinical assessments

A senior psychiatrist interviewed every patient individually and recorded the Clinical Global Impression (CGI) score at baseline and at the end of the rTMS trial. The severity of AH was assessed using the Hallucination Change Scale (HCS).3 The severity of AH at baseline was assigned a score of 10. After rTMS, lack of AH was scored as 0, same severity of AH was scored as 10, doubled severity of AH was scored as 20, and so on.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

No somatic complaints were reported during and after rTMS. When the study was completed, three patients reported a ≥50%, two patients a 30%, and one patient a 10% reduction of AH, but the extent of AH reduction diminished gradually with time (Table 1).

Table 1.  Patient characteristics and clinical data
No.Antipsychotics (mg/day)CGIHCS
BaselineEndEndOne-week follow upOne-month follow up
  • A score of 10 is assigned at baseline. For subsequent assessments, the HCS ranges from 0 (no AH) to 20 (AH twice as severe as baseline).

  • AH, auditory hallucination; CGI, Clinical Global Impression; HCS, Hallucination Change Scale.

1Olanzapine (20) + sulpiride (400)55101010
2Haloperidol (20)543510
3Trifluoperazine (50)55457
4Flupenthixol (9)55558
5Amisulpiride (300)55779
6Amisulpiride (800)55779
7Clozapine (350) + sulpiride (800)66101010
8Clozapine (400)6691010

In sham stimulation, patients only lay on the bed without exposure to magnetic stimulation. We compared HRV parameters before and after sham stimulation on dependent t-test to evaluate the effects of lying quietly for 16 min on CAF. The R–R interval, variation in the R–R interval and HF all increased, but LF/HF decreased. Therefore, controlling for the effects of lying down throughout rTMS was required while assessing the effects of rTMS on CAF. We then calculated changes of HRV parameters after sham stimulation and after active stimulation, respectively, and compared the two groups of data on independent t-test. With sham control, we found that LF/HF was significantly elevated after active magnetic stimulation (active group, 0.004 ± 0.88; sham group, −0.54 ± 0.65 [In(ratio)], d.f. = 46, t = 2.18, P = 0.034, two-tailed).

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The present study showed that rTMS had partial efficacy on AH in schizophrenia and rTMS was also well-tolerated, although the extent of AH reduction diminished gradually with time. Hence, rTMS may be a good add-on treatment for medication-resistant schizophrenia patients with AH. The efficacy of rTMS in the present study seemed much lower than that reported by Hoffman et al. Severity of illness may play an important role: the Hoffman et al. patients had CGI scores ranging from 2 to 3 but the present patients' CGI scores ranged from 5 to 6. Severity of illness may therefore be negatively correlated with the efficacy of rTMS. Also, patients who experienced a ≥50% reduction in AH in the present study were all taking typical antipsychotics, so schizophrenia patients' current medication may also have contributed to the variable efficacy of rTMS. The present sample size, however, was too small to make any definite conclusion.

Regarding the immediate effects of rTMS on CAF, the sham stimulation increased vagal activity and decreased sympathetic modulation. The net effects of rTMS on CAF were little on vagal activity but there was significant elevation of sympathetic modulation. These findings differed from those caused by ECT, possibly owing to different mechanisms between rTMS and ECT.

There were several limitations to the present study: first, there was no placebo control group, so some patients may have overestimated the extent of AH reduction because of placebo effects. Second, stimulation was focused on the left temporoparietal cortex, and stimulation of other brain areas may lead to different results. Also, different rTMS protocols may bring about different results. Third, the present subjects were all medicated schizophrenia patients; therefore, overgeneralization of the results to other groups is not recommended.

To our best of our knowledge, this is the first study to assess the immediate impact of rTMS on CAF. Repetitive TMS to the left temporoparietal cortex showed some efficacy in treating AH in schizophrenia patients. Limited by the small sample size, we cannot report any definite conclusions, but we hope that replication studies with more patients or patients with different severity of illness will be conducted in the near future.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Shergill SS, Murray RM, McGuire PK. Auditory hallucinations: A review of psychological treatments. Schizophr. Res. 1998; 32: 137150.
  • 2
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  • 3
    Hoffman RE, Hawkins KA, Gueorguieva R et al. Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Arch. Gen. Psychiatry 2003; 60: 4956.
  • 4
    Hoffman RE, Gueorguieva R, Hawkins KA et al. Temporoparietal transcranial magnetic stimulation for auditory hallucinations: Safety, efficacy and moderators in a fifty patient sample. Biol. Psychiatry 2005; 58: 97104.
  • 5
    Lai IC, Wang YC, Yang CC, Kuo TB, Shieh KR. Immediate impact of electroconvulsive therapy on cardiac autonomic function in schizophrenia: A preliminary study. Schizophr. Res. 2008; 100: 353355.
  • 6
    Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: Standards of measurement, physiological interpretation and clinical use. Circulation 1996; 93: 10431065.
  • 7
    Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: Report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr. Clin. Neurophysiol. 1998; 108: 116.
  • 8
    Kuo TB, Yien HW, Hseu SS et al. Diminished vasomotor component of systemic arterial pressure signals and baroreflex in brain death. Am. J. Physiol. 1997; 273: H1291H1298.