Brain Stimulation 7 (2014) 813e816
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
A Negative Pilot Study of Daily Bimodal Transcranial Direct Current Stimulation in Schizophrenia Paul B. Fitzgerald a, *, Susan McQueen a, Zafiris J. Daskalakis b, Kate E. Hoy a a b
Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Melbourne, Victoria 3004, Australia Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 July 2014 Received in revised form 6 August 2014 Accepted 6 August 2014 Available online 27 October 2014
Background: A small number of studies conducted to date have suggested that transcranial direct current stimulation (tDCS) applied to the temporoparietal cortex may reduce auditory hallucinations in patients with schizophrenia. Prefrontal brain stimulation with other methods, has also been shown to potentially improve the negative symptoms of this disorder. Objective: To investigate the therapeutic potential of daily bimodal tDCS: anodal stimulation to the prefrontal cortex and cathodal stimulation to the temporoparietal junction in patients with persistent hallucinations and negative symptoms of schizophrenia. Methods: We conducted two small randomized double-blind controlled trials comparing bimodal tDCS to sham stimulation. In one study, stimulation was provided unilaterally, in the second study it was provided bilaterally. Results: Neither unilateral nor bilateral tDCS resulted in a substantial change in either hallucinations or negative symptoms. Stimulation was well tolerated without side-effects. Conclusion: Daily tDCS does not appear to have substantial potential in the treatment of hallucinations or negative symptoms and further research should investigate higher doses of stimulation or more frequently applied treatment schedules. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Repetitive transcranial direct current stimulation Schizophrenia Auditory hallucinations Negative symptoms Prefrontal cortex
Introduction Schizophrenia (SCZ) is a debilitating disease which affects approximately 1% of the population. Despite there being a range of effective medications available for the treatment of schizophrenia, several symptom types fail to respond well to treatment. For example, a significant proportion of patients with auditory hallucinations will continue to experience these symptoms in spite of optimal antipsychotic medications. In addition, the negative symptoms of schizophrenia have typically proven difficult to ameliorate with antipsychotic medications. Research is progressively enhancing our understanding of the brain mechanisms that underlie the various symptoms of schizophrenia. For example, a number of lines of research have suggested that auditory processing regions of the brain, close to the temporoparietal junction, may be overactive whilst individuals are experiencing auditory
* Corresponding author. Monash Alfred Psychiatry Research Centre, Level 4, 607 St Kilda Road, Melbourne, Victoria 3004, Australia. Tel.: þ61 3 9076 6552; fax: þ61 3 9076 6588. E-mail address: paul.fi[email protected] (P.B. Fitzgerald). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2014.08.002
hallucinations [1,2]. In addition, a number of studies have found an association between negative symptoms, including blunted affect and cognitive deficits, and reduced activation in prefrontal areas, particularly the left prefrontal cortex [3e7]. Treatments which could target both these areas would be of considerable value. Transcranial direct current stimulation (tDCS) is a novel, non-invasive and non-convulsive technique for altering brain function. It involves the application of a small current (typically 1e2 mA) between an anodal and cathodal electrode which are placed on the scalp. Typically, an increase in neuronal excitability occurs under the anode, and a decrease under the cathode, probably through depolarization and hyperpolarization of neurons, respectively [8]. It has been shown to be safe in several experimental and clinical trials [9] and potential therapeutic benefits have been demonstrated in depression, pain disorders, tinnitus and motor impairment post stroke [10,11]. Recently, a limited amount of research has investigated the potential use of tDCS in the treatment of patients with schizophrenia. For example, Brunelin et al. demonstrated a reduction in hallucination severity when tDCS was provided twice daily over a five day period of time [12]. In this study, cathodal tDCS was applied to the left temporoparietal cortex with the presumption that this
814
P.B. Fitzgerald et al. / Brain Stimulation 7 (2014) 813e816
would reduce excessive activity thought to underlie auditory hallucinations. A series of other cases have also reported potential improvements in hallucinations with similar applications of tDCS (for example Refs. [13e15]). One feature of the application of tDCS is that both anodal and cathodal stimulation (increasing and decreasing regional brain activity) can be applied simultaneously. For this reason we chose to investigate the application of cathodal tDCS to the temporoparietal cortex (targeting auditory hallucinations) combined with anodal stimulation to dorsal prefrontal brain regions which was hypothesized to potentially improve negative or cognitive symptoms of schizophrenia. We conducted two pilot studies: one where tDCS was applied to left sided brain regions only and one where tDCS was applied bilaterally. The focus in these studies was on the provision of daily rather than twice daily sessions to see if this produced equivalent benefits. We investigated bilateral as well as unilateral stimulation as transcranial magnetic stimulation studies have suggested the potential for both left and right sided stimulation approaches in the treatment of hallucinations (e.g. Ref. [16]). Methods We conducted two pilot studies with identical methodology except for an alteration in the method of provision of tDCS: in one study left unilateral tDCS was assessed, in the second bilateral tDCS was used (Fig. 1). Each study involved a randomized, sham controlled parallel group design. In both protocols blinded tDCS was provided for 15 daily sessions over three consecutive weeks. Individuals were randomized on a computer-generated list with the information stored on a central computer: codes were allocated for active and sham stimulation (separate for each patient) and these codes used to activate the tDCS machine. As such, both the patient and the clinician administering the tDCS stimulation were blinded to the treatment group. Subjects Patients with schizophrenia or schizoaffective disorder (diagnosis confirmed with the M.I.N.I) between the ages of 18 and 65 were included. Patients were required to have persistent hallucinations and negative symptoms with a failure to respond to at least two adequate trials of antipsychotic medication. Patients were excluded if they had a concurrent axis I diagnosis, and unstable medical or neurological illnesses or patients who were taking carbamazepine, or who are pregnant.
tDCS tDCS was applied using an Eldith Stimulator Plus (neuroConn GBH) delivering direct current through two surface electrodes (35 cm2 saline soaked sponges). Stimulation was delivered (20 min, ramp of 120 s and ramp down of 15 s) in two conditions: 2 mA, and sham. Anodal stimulation was given to the DLPFC localized using F3/4 EEG site (10-20 EEG system) and the cathode was placed over the temporoparietal area (TP3/4 EEG site). Sham stimulation involved a ramp up of stimulation and 30 s of stimulation prior to stimulation off set. Assessments Symptoms were assessed with the Positive and Negative Symptom Scale (PANSS) [15], the Scale for the Assessment of Negative Symptoms (SANS) [17] and the Calgary Depression Scale [18]. In addition, cognitive performance was assessed with the forwards and backwards digit span (assessment of verbal working memory) and block spatial span (spatial working memory) tests, the N-back task, Tower of London planning task, FAS verbal fluency task and the trail making task (A&B). Analysis We used a series of t-tests to assess difference in change scores in AH, positive and negative symptoms over time between the groups. Results Subjects 24 patients (15 male, 9 female, mean age ¼ 39.3 11.7 years) were randomized and received at least one active treatment. 17 had a diagnosis of schizophrenia and 7 had a diagnosis of schizoaffective disorder. The mean age of diagnosis was 23.2 8.4 years. 11 received bilateral and 13 received unilateral double-blind stimulation. Clinical outcomes There was no difference in reduction of AH severity between active and sham stimulation for the group as a whole, for bilateral or unilateral tDCS (see Table 1). There was also no difference in
Figure 1. Schematic showing the tDCS set up for A) bilateral tDCS and B) unilateral tDCS.
P.B. Fitzgerald et al. / Brain Stimulation 7 (2014) 813e816
815
Table 1 PANSS auditory hallucination (AH) item, Positive, Negative subscales and Total scores and Total SANS scores for the sample as a whole and the bilateral and negative trials separately. t test values are for differences in baseline to end of treatment change scores between the groups. Baseline
Total group
PANSS AH Score PANSS Positive PANSS Negative PANSS Total SANS Total
Bilateral tDCS
PANSS AH Score PANSS Positive PANSS Negative PANSS Total SANS Total
Unilateral tDCS
PANSS AH Score PANSS Positive PANSS Negative PANSS Total SANS Total
Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham
End of Treatment
Mean
SD
Mean
SD
3.7 3.4 13.2 11.1 17.1 20.8 80.6 77.5 47.8 55.5 3.8 3.5 12.8 11.2 12.0 12.0 67.6 79.7 30.2 55.5 3.6 3.2 13.5 11.0 20.2 21.8 88.8 75.0 58.8 55.6
2.0 1.7 3.6 4.5 5.5 6.1 14.5 19.0 17.3 16.1 1.6 1.8 2.7 5.0 3.3 6.8 12.8 22.6 12.4 19.6 2.3 1.8 4.2 4.4 3.9 5.8 8.5 15.8 8.3 13.0
3.1 3.2 11.7 10.8 16.6 19.4 75.7 75.2 48.2 53.1 3.3 3.4 10.5 10.6 10.0 19.0 57.2 78.4 29.6 51.7 3.0 3.0 12.3 11.0 19.9 19.8 84.9 72.0 59.8 54.8
2.0 1.7 3.6 4.3 5.9 5.2 17.1 18.6 18.3 13.7 2.1 1.7 4.4 4.8 2.2 6.0 12.6 22.0 11.7 16.3 2.1 2.0 3.4 4.2 3.9 5.0 9.9 16.4 9.8 11.3
change in total PANSS scores, PANSS positive symptoms, PANSS negative symptoms or SANS total symptoms for the group as a whole for bilateral or unilateral tDCS (Table 1). Side effects No major adverse events were reported. 6 patients in the active group (2 bilateral, 4 unilateral) reported itchiness under the electrodes compared to 4 in the sham group (91 bilateral, 2 unilateral). 1 patient in each group reported headaches and 2 sham patients described non-specific site discomfort. Discussion In contrast to our initial expectation, in this study we failed to find any therapeutic effects of tDCS applied concurrently to the prefrontal cortex and temporoparietal junction. When tDCS was applied unilaterally or bilaterally we saw no differences in auditory hallucination severity or the severity of positive or negative symptoms. tDCS was well tolerated in this clinical population but produced no therapeutic benefits. There are several reasons why we may have failed to demonstrate therapeutic effects in contrast to a number of recent reports which have investigated the therapeutic impact of tDCS in schizophrenia. Therapeutic effects have been reported in a number of case reports of tDCS predominately on auditory hallucinations [13,15,19]. Brunelin et al. found a significant reduction in AH severity with 2 mA tDCS [12]. However, in contrast to our study, they provided stimulation twice daily over a 5 day period of time, while we provided once daily sessions for a period of three weeks. This more intensive application of tDCS may be therapeutically significant, especially as studies in motor cortex are showing that repeated tDCS sessions at short interval may be more effect than single (or
t
df
P
1.1
22
0.3
1.4
22
0.2
1.1
22
0.3
22
0.5
1.2
22
0.3
1.0
9
0.3
0.8
9
0.5
0.5
9
0.6
0.6
9
0.6
1.0
9
0.3
0.2
11
0.9
1.1
11
0.3
0.9
11
0.4
0.2
11
0.8
0.5
11
0.6
0.67
presumably more widely spaced individual) sessions [20]. It is clearly too early to make conclusions as to the optimal spacing of tDCS sessions in the treatment of schizophrenia. However, further research should be addressed toward defining what the optimal spacing of treatment sessions might prove to be. This could include more intensive protocols than those used to date, for example three or more times per day, especially for inpatients, although clearly safety will need to be addressed with these approaches. A second factor that might have contributed to the negative results in our study was the considerable degree of heterogeneity in the patient sample. Although we were focused on therapeutic effects in relationship to hallucinations and negative symptoms, a number of the patients had broader symptom profiles, including the persistence of delusions and other positive symptoms. If an effect on isolated symptoms such as hallucinations is present, it may be difficult to determine this in patients with more mixed symptoms. Clearly tDCS was well tolerated in this patient sample. We saw no significant adverse events and the rate of less serious side effects did not really significantly differ between the sham and active treatment groups. This is in keeping with the broadly positive safety profile of tDCS. There were a number of substantial limitations of this pilot study. The first was clearly the sample size for both the pooled and individual analyses. The change in AH scores were very similar in the pooled and individual comparisons: around 0.6 for active and 0.2 for sham stimulation. For this very modest difference and the variance seen, a sample size of around 200 would be required to demonstrate a significant effect, a study size clearly beyond what we were able to do. As discussed above, there was also a degree of heterogeneity in the patient sample, and furthermore, we investigated two forms of application of tDCS in the one study. However, despite these limitations, we saw no therapeutic signal that would
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P.B. Fitzgerald et al. / Brain Stimulation 7 (2014) 813e816
suggest that pursuing daily tDCS is likely to be useful and further studies should concentrate on more intensive [12] and perhaps longer treatment protocols. Future studies should also aim to maximize the efficacy of the application of tDCS: for example via the optimization of electrode size and potential use of intermittent and other novel protocols [21,22]. Acknowledgments PBF is supported by an NHMRC practitioner fellowship. PBF has received equipment for research from Medtronic Ltd, Cervel Neurotech, Brainsway Ltd and Magventure A/S. He has received funding for research activities from Cervel Neurotech. KEH has nothing to declare. In the last 5 years, ZJD received research and equipment inkind support for an investigator-initiated study through Brainsway Inc and a travel allowance through Merck. ZJD has also received speaker funding through Sepracor Inc, AstraZeneca and served on the advisory board for Hoffmann-La Roche Limited and Merck and received speaker support from Eli Lilly. This work was supported by the Ontario Mental Health Foundation, the Canadian Institutes of Health Research, the Brain and Behaviour Research Foundation and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. References [1] Dierks T, Linden DE, Jandl M, et al. Activation of Heschl’s gyrus during auditory hallucinations. Neuron 1999;22(3):615e21. [2] Ropohl A, Sperling W, Elstner S, et al. Cortical activity associated with auditory hallucinations. Neuroreport 2004;15(3):523e6. [3] Vaiva G, Cottencin O, Llorca PM, et al. Regional cerebral blood flow in deficit/ nondeficit types of schizophrenia according to SDS criteria. Prog Neuropsychopharmacol Biol Psychiatry 2002;26(3):481e5. [4] Liu Z, Tam W-CC, Xie Y, Zhao J. The relationship between regional cerebral blood flow and the Wisconsin Card Sorting Test in negative schizophrenia. Psychiatry Clin Neurosci 2002;56(1):3e7. [5] Wang CS-M, Yang Y-K, Chen M, Chiu N-T, Yeh T-L, Lee IH. Negative symptoms and regional cerebral blood flow in patients with schizophrenia: a single photon emission computed tomography study. Kaohsiung J Med Sci 2003;19(9):464e9.
[6] Weiss EM, Golaszewski S, Mottaghy FM, et al. Brain activation patterns during a selective attention test-a functional MRI study in healthy volunteers and patients with schizophrenia. Psychiatry Res 2003;123(1):1e15. [7] Li X, Tang J, Wu Z, Zhao G, Liu C, George MS. SPECT study of Chinese schizophrenic patients suggests that cerebral hypoperfusion and laterality exist in different ethnic groups. World J Biol Psychiatry 2005;6(2):98e106. [8] Nitsche MA, Fricke K, Henschke U, et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol 2003;553(Pt 1):293e301. [9] Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clin Neurophysiol 2003;114(11):2220e2. author reply 2222-3. [10] Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP, Pascual-Leone A. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord 2006;8(2):203e4. [11] Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol 2006;117(4):845e50. [12] Vaseghi B, Zoghi M, Jaberzadeh S. Does anodal transcranial direct current stimulation modulate sensory perception and pain? A meta-analysis study. Clin Neurophysiol 2014;125:1847e58. [13] Khan A, Lindenmayer JP, Opler M, Yavorsky C, Rothman B, Lucic L. A new Integrated Negative Symptom structure of the Positive and Negative Syndrome Scale (PANSS) in schizophrenia using item response analysis. Schizophr Res 2013;150(1):185e96. [14] Shiozawa P, da Silva ME, Cordeiro Q, Fregni F, Brunoni AR. Transcranial direct current stimulation (tDCS) for the treatment of persistent visual and auditory hallucinations in schizophrenia: a case study. Brain Stimul 2013;6:831e3. [15] Kay SR. Positive-negative symptom assessment in schizophrenia: psychometric issues and scale comparison. Psychiatr Q 1990;61(3):163e78. [16] Lee SH, Kim W, Chung YC, et al. A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatmentrefractory auditory hallucinations. Neurosci Lett 2005;376(3):177e81. [17] Andreasen NC. Improvement of negative symptoms: concepts, definition and assessment. Int Clin Psychopharmacol 1997;12(Suppl. 2):S7e10. [18] Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry Suppl 1993;(22): 39e44. [19] Preston NJ, Harrison TJ. The brief symptom inventory and the positive and negative syndrome scale: discriminate validity between a self-reported and observational measure of psychopathology. Compr Psychiatry 2003;44(3): 220e6. [20] Brinkworth RS, Tuncer M, Tucker KJ, Jaberzadeh S, Turker KS. Standardization of H-reflex analyses. J Neurosci Methods 2007;162(1e2):1e7. [21] Jaberzadeh S, Bastani A, Zoghi M. Anodal transcranial pulsed current stimulation: a novel technique to enhance corticospinal excitability. Clin Neurophysiol 2014;125(2):344e51. [22] Bastani A, Jaberzadeh S. a-tDCS differential modulation of corticospinal excitability: the effects of electrode size. Brain Stimul 2013;6(6):932e7.
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
A Negative Pilot Study of Daily Bimodal Transcranial Direct Current Stimulation in Schizophrenia Paul B. Fitzgerald a, *, Susan McQueen a, Zafiris J. Daskalakis b, Kate E. Hoy a a b
Monash Alfred Psychiatry Research Centre, The Alfred and Monash University Central Clinical School, Melbourne, Victoria 3004, Australia Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 July 2014 Received in revised form 6 August 2014 Accepted 6 August 2014 Available online 27 October 2014
Background: A small number of studies conducted to date have suggested that transcranial direct current stimulation (tDCS) applied to the temporoparietal cortex may reduce auditory hallucinations in patients with schizophrenia. Prefrontal brain stimulation with other methods, has also been shown to potentially improve the negative symptoms of this disorder. Objective: To investigate the therapeutic potential of daily bimodal tDCS: anodal stimulation to the prefrontal cortex and cathodal stimulation to the temporoparietal junction in patients with persistent hallucinations and negative symptoms of schizophrenia. Methods: We conducted two small randomized double-blind controlled trials comparing bimodal tDCS to sham stimulation. In one study, stimulation was provided unilaterally, in the second study it was provided bilaterally. Results: Neither unilateral nor bilateral tDCS resulted in a substantial change in either hallucinations or negative symptoms. Stimulation was well tolerated without side-effects. Conclusion: Daily tDCS does not appear to have substantial potential in the treatment of hallucinations or negative symptoms and further research should investigate higher doses of stimulation or more frequently applied treatment schedules. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Repetitive transcranial direct current stimulation Schizophrenia Auditory hallucinations Negative symptoms Prefrontal cortex
Introduction Schizophrenia (SCZ) is a debilitating disease which affects approximately 1% of the population. Despite there being a range of effective medications available for the treatment of schizophrenia, several symptom types fail to respond well to treatment. For example, a significant proportion of patients with auditory hallucinations will continue to experience these symptoms in spite of optimal antipsychotic medications. In addition, the negative symptoms of schizophrenia have typically proven difficult to ameliorate with antipsychotic medications. Research is progressively enhancing our understanding of the brain mechanisms that underlie the various symptoms of schizophrenia. For example, a number of lines of research have suggested that auditory processing regions of the brain, close to the temporoparietal junction, may be overactive whilst individuals are experiencing auditory
* Corresponding author. Monash Alfred Psychiatry Research Centre, Level 4, 607 St Kilda Road, Melbourne, Victoria 3004, Australia. Tel.: þ61 3 9076 6552; fax: þ61 3 9076 6588. E-mail address: paul.fi[email protected] (P.B. Fitzgerald). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2014.08.002
hallucinations [1,2]. In addition, a number of studies have found an association between negative symptoms, including blunted affect and cognitive deficits, and reduced activation in prefrontal areas, particularly the left prefrontal cortex [3e7]. Treatments which could target both these areas would be of considerable value. Transcranial direct current stimulation (tDCS) is a novel, non-invasive and non-convulsive technique for altering brain function. It involves the application of a small current (typically 1e2 mA) between an anodal and cathodal electrode which are placed on the scalp. Typically, an increase in neuronal excitability occurs under the anode, and a decrease under the cathode, probably through depolarization and hyperpolarization of neurons, respectively [8]. It has been shown to be safe in several experimental and clinical trials [9] and potential therapeutic benefits have been demonstrated in depression, pain disorders, tinnitus and motor impairment post stroke [10,11]. Recently, a limited amount of research has investigated the potential use of tDCS in the treatment of patients with schizophrenia. For example, Brunelin et al. demonstrated a reduction in hallucination severity when tDCS was provided twice daily over a five day period of time [12]. In this study, cathodal tDCS was applied to the left temporoparietal cortex with the presumption that this
814
P.B. Fitzgerald et al. / Brain Stimulation 7 (2014) 813e816
would reduce excessive activity thought to underlie auditory hallucinations. A series of other cases have also reported potential improvements in hallucinations with similar applications of tDCS (for example Refs. [13e15]). One feature of the application of tDCS is that both anodal and cathodal stimulation (increasing and decreasing regional brain activity) can be applied simultaneously. For this reason we chose to investigate the application of cathodal tDCS to the temporoparietal cortex (targeting auditory hallucinations) combined with anodal stimulation to dorsal prefrontal brain regions which was hypothesized to potentially improve negative or cognitive symptoms of schizophrenia. We conducted two pilot studies: one where tDCS was applied to left sided brain regions only and one where tDCS was applied bilaterally. The focus in these studies was on the provision of daily rather than twice daily sessions to see if this produced equivalent benefits. We investigated bilateral as well as unilateral stimulation as transcranial magnetic stimulation studies have suggested the potential for both left and right sided stimulation approaches in the treatment of hallucinations (e.g. Ref. [16]). Methods We conducted two pilot studies with identical methodology except for an alteration in the method of provision of tDCS: in one study left unilateral tDCS was assessed, in the second bilateral tDCS was used (Fig. 1). Each study involved a randomized, sham controlled parallel group design. In both protocols blinded tDCS was provided for 15 daily sessions over three consecutive weeks. Individuals were randomized on a computer-generated list with the information stored on a central computer: codes were allocated for active and sham stimulation (separate for each patient) and these codes used to activate the tDCS machine. As such, both the patient and the clinician administering the tDCS stimulation were blinded to the treatment group. Subjects Patients with schizophrenia or schizoaffective disorder (diagnosis confirmed with the M.I.N.I) between the ages of 18 and 65 were included. Patients were required to have persistent hallucinations and negative symptoms with a failure to respond to at least two adequate trials of antipsychotic medication. Patients were excluded if they had a concurrent axis I diagnosis, and unstable medical or neurological illnesses or patients who were taking carbamazepine, or who are pregnant.
tDCS tDCS was applied using an Eldith Stimulator Plus (neuroConn GBH) delivering direct current through two surface electrodes (35 cm2 saline soaked sponges). Stimulation was delivered (20 min, ramp of 120 s and ramp down of 15 s) in two conditions: 2 mA, and sham. Anodal stimulation was given to the DLPFC localized using F3/4 EEG site (10-20 EEG system) and the cathode was placed over the temporoparietal area (TP3/4 EEG site). Sham stimulation involved a ramp up of stimulation and 30 s of stimulation prior to stimulation off set. Assessments Symptoms were assessed with the Positive and Negative Symptom Scale (PANSS) [15], the Scale for the Assessment of Negative Symptoms (SANS) [17] and the Calgary Depression Scale [18]. In addition, cognitive performance was assessed with the forwards and backwards digit span (assessment of verbal working memory) and block spatial span (spatial working memory) tests, the N-back task, Tower of London planning task, FAS verbal fluency task and the trail making task (A&B). Analysis We used a series of t-tests to assess difference in change scores in AH, positive and negative symptoms over time between the groups. Results Subjects 24 patients (15 male, 9 female, mean age ¼ 39.3 11.7 years) were randomized and received at least one active treatment. 17 had a diagnosis of schizophrenia and 7 had a diagnosis of schizoaffective disorder. The mean age of diagnosis was 23.2 8.4 years. 11 received bilateral and 13 received unilateral double-blind stimulation. Clinical outcomes There was no difference in reduction of AH severity between active and sham stimulation for the group as a whole, for bilateral or unilateral tDCS (see Table 1). There was also no difference in
Figure 1. Schematic showing the tDCS set up for A) bilateral tDCS and B) unilateral tDCS.
P.B. Fitzgerald et al. / Brain Stimulation 7 (2014) 813e816
815
Table 1 PANSS auditory hallucination (AH) item, Positive, Negative subscales and Total scores and Total SANS scores for the sample as a whole and the bilateral and negative trials separately. t test values are for differences in baseline to end of treatment change scores between the groups. Baseline
Total group
PANSS AH Score PANSS Positive PANSS Negative PANSS Total SANS Total
Bilateral tDCS
PANSS AH Score PANSS Positive PANSS Negative PANSS Total SANS Total
Unilateral tDCS
PANSS AH Score PANSS Positive PANSS Negative PANSS Total SANS Total
Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham Active Sham
End of Treatment
Mean
SD
Mean
SD
3.7 3.4 13.2 11.1 17.1 20.8 80.6 77.5 47.8 55.5 3.8 3.5 12.8 11.2 12.0 12.0 67.6 79.7 30.2 55.5 3.6 3.2 13.5 11.0 20.2 21.8 88.8 75.0 58.8 55.6
2.0 1.7 3.6 4.5 5.5 6.1 14.5 19.0 17.3 16.1 1.6 1.8 2.7 5.0 3.3 6.8 12.8 22.6 12.4 19.6 2.3 1.8 4.2 4.4 3.9 5.8 8.5 15.8 8.3 13.0
3.1 3.2 11.7 10.8 16.6 19.4 75.7 75.2 48.2 53.1 3.3 3.4 10.5 10.6 10.0 19.0 57.2 78.4 29.6 51.7 3.0 3.0 12.3 11.0 19.9 19.8 84.9 72.0 59.8 54.8
2.0 1.7 3.6 4.3 5.9 5.2 17.1 18.6 18.3 13.7 2.1 1.7 4.4 4.8 2.2 6.0 12.6 22.0 11.7 16.3 2.1 2.0 3.4 4.2 3.9 5.0 9.9 16.4 9.8 11.3
change in total PANSS scores, PANSS positive symptoms, PANSS negative symptoms or SANS total symptoms for the group as a whole for bilateral or unilateral tDCS (Table 1). Side effects No major adverse events were reported. 6 patients in the active group (2 bilateral, 4 unilateral) reported itchiness under the electrodes compared to 4 in the sham group (91 bilateral, 2 unilateral). 1 patient in each group reported headaches and 2 sham patients described non-specific site discomfort. Discussion In contrast to our initial expectation, in this study we failed to find any therapeutic effects of tDCS applied concurrently to the prefrontal cortex and temporoparietal junction. When tDCS was applied unilaterally or bilaterally we saw no differences in auditory hallucination severity or the severity of positive or negative symptoms. tDCS was well tolerated in this clinical population but produced no therapeutic benefits. There are several reasons why we may have failed to demonstrate therapeutic effects in contrast to a number of recent reports which have investigated the therapeutic impact of tDCS in schizophrenia. Therapeutic effects have been reported in a number of case reports of tDCS predominately on auditory hallucinations [13,15,19]. Brunelin et al. found a significant reduction in AH severity with 2 mA tDCS [12]. However, in contrast to our study, they provided stimulation twice daily over a 5 day period of time, while we provided once daily sessions for a period of three weeks. This more intensive application of tDCS may be therapeutically significant, especially as studies in motor cortex are showing that repeated tDCS sessions at short interval may be more effect than single (or
t
df
P
1.1
22
0.3
1.4
22
0.2
1.1
22
0.3
22
0.5
1.2
22
0.3
1.0
9
0.3
0.8
9
0.5
0.5
9
0.6
0.6
9
0.6
1.0
9
0.3
0.2
11
0.9
1.1
11
0.3
0.9
11
0.4
0.2
11
0.8
0.5
11
0.6
0.67
presumably more widely spaced individual) sessions [20]. It is clearly too early to make conclusions as to the optimal spacing of tDCS sessions in the treatment of schizophrenia. However, further research should be addressed toward defining what the optimal spacing of treatment sessions might prove to be. This could include more intensive protocols than those used to date, for example three or more times per day, especially for inpatients, although clearly safety will need to be addressed with these approaches. A second factor that might have contributed to the negative results in our study was the considerable degree of heterogeneity in the patient sample. Although we were focused on therapeutic effects in relationship to hallucinations and negative symptoms, a number of the patients had broader symptom profiles, including the persistence of delusions and other positive symptoms. If an effect on isolated symptoms such as hallucinations is present, it may be difficult to determine this in patients with more mixed symptoms. Clearly tDCS was well tolerated in this patient sample. We saw no significant adverse events and the rate of less serious side effects did not really significantly differ between the sham and active treatment groups. This is in keeping with the broadly positive safety profile of tDCS. There were a number of substantial limitations of this pilot study. The first was clearly the sample size for both the pooled and individual analyses. The change in AH scores were very similar in the pooled and individual comparisons: around 0.6 for active and 0.2 for sham stimulation. For this very modest difference and the variance seen, a sample size of around 200 would be required to demonstrate a significant effect, a study size clearly beyond what we were able to do. As discussed above, there was also a degree of heterogeneity in the patient sample, and furthermore, we investigated two forms of application of tDCS in the one study. However, despite these limitations, we saw no therapeutic signal that would
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suggest that pursuing daily tDCS is likely to be useful and further studies should concentrate on more intensive [12] and perhaps longer treatment protocols. Future studies should also aim to maximize the efficacy of the application of tDCS: for example via the optimization of electrode size and potential use of intermittent and other novel protocols [21,22]. Acknowledgments PBF is supported by an NHMRC practitioner fellowship. PBF has received equipment for research from Medtronic Ltd, Cervel Neurotech, Brainsway Ltd and Magventure A/S. He has received funding for research activities from Cervel Neurotech. KEH has nothing to declare. In the last 5 years, ZJD received research and equipment inkind support for an investigator-initiated study through Brainsway Inc and a travel allowance through Merck. ZJD has also received speaker funding through Sepracor Inc, AstraZeneca and served on the advisory board for Hoffmann-La Roche Limited and Merck and received speaker support from Eli Lilly. This work was supported by the Ontario Mental Health Foundation, the Canadian Institutes of Health Research, the Brain and Behaviour Research Foundation and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. References [1] Dierks T, Linden DE, Jandl M, et al. Activation of Heschl’s gyrus during auditory hallucinations. Neuron 1999;22(3):615e21. [2] Ropohl A, Sperling W, Elstner S, et al. Cortical activity associated with auditory hallucinations. Neuroreport 2004;15(3):523e6. [3] Vaiva G, Cottencin O, Llorca PM, et al. Regional cerebral blood flow in deficit/ nondeficit types of schizophrenia according to SDS criteria. Prog Neuropsychopharmacol Biol Psychiatry 2002;26(3):481e5. [4] Liu Z, Tam W-CC, Xie Y, Zhao J. The relationship between regional cerebral blood flow and the Wisconsin Card Sorting Test in negative schizophrenia. Psychiatry Clin Neurosci 2002;56(1):3e7. [5] Wang CS-M, Yang Y-K, Chen M, Chiu N-T, Yeh T-L, Lee IH. Negative symptoms and regional cerebral blood flow in patients with schizophrenia: a single photon emission computed tomography study. Kaohsiung J Med Sci 2003;19(9):464e9.
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