The efficacy of cerebellar vermal deep high frequency (theta range) repetitive transcranial magnetic stimulation (rTMS) in schizophrenia: A randomized rater blind-sham controlled study

Psychiatry Research 243 (2016) 413–420

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The efficacy of cerebellar vermal deep high frequency (theta range) repetitive transcranial magnetic stimulation (rTMS) in schizophrenia: A randomized rater blind-sham controlled study Shobit Garg a, Vinod Kumar Sinha b, Sai Krishna Tikka b,n, Preeti Mishra a, Nishant Goyal b a b

Department of Psychiatry, Shri Guru Ram Rai Institute of Medical & Health Sciences, Dehradun, Uttarakhand, India KS Mani Center for Cognitive Neurosciences and Department of Psychiatry, Central Institute of Psychiatry, Kanke, Ranchi, Jharkhand 834006, India

art ic l e i nf o

a b s t r a c t

Article history: Received 11 July 2016 Accepted 11 July 2016 Available online 16 July 2016

Repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic for schizophrenia. Treatment effects of rTMS have been variable across different symptom clusters, with negative symptoms showing better response, followed by auditory hallucinations. Cerebellum, especially vermis and its abnormalities (both structural and functional) have been implicated in cognitive, affective and positive symptoms of schizophrenia. rTMS to this alternate site has been suggested as a novel target for treating patients with this disorder. Hypothesizing cerebellar vermal magnetic stimulation as an adjunct to treat schizophrenia psychopathology, we conducted a double blind randomized sham controlled rTMS study. In this study, forty patients were randomly allocated (using block randomization method) to active high frequency (theta patterned) rTMS (n¼20) and sham (n¼ 20) groups. They received 10 sessions over 2 weeks. The Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) scores were assessed at baseline, after last session and at 4 weeks (2 weeks post-rTMS). We found a significantly greater improvement in the group receiving active rTMS sessions, compared to the sham group on negative symptoms, and depressive symptoms. We conclude that cerebellar stimulation can be used as an effective adjunct to treat negative and affective symptoms. & 2016 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cerebellum Transcranial magnetic stimulation Schizophrenia

1. Introduction Conventional management with pharmacological interventions in patients with schizophrenia, although successful to an extent in treatment of positive symptoms, has been a futile exercise in considerable number of cases, especially in the treatment of negative symptoms (Tsapakis et al., 2015). Successful management in schizophrenia cases remains a major unmet health need. Besides newer antipsychotics, meta-analytic studies on adjunctive treatment with agents like Ginkgo biloba, oxytocin and other sex hormones, modafinil/ armodafinil, minocycline, antioxidant agents, antiglucocorticoid agents, cGMP, etc, have been undertaken (Chen et al., 2015; Heringa et al., 2015; Andrade et al., 2015; Oya et al., 2014; Magalhães et al., 2016; Garner et al., 2016; Shim et al., 2016). While, minocycline and phosphodiesterase inhibitors have been found to be especially effective for negative and cognitive symptoms, and estrogen found effective in women, a negative evidence exists for modafinil/ armodafinil; other modalities lack significant n

Corresponding author. E-mail address: [email protected] (S.K. Tikka).

http://dx.doi.org/10.1016/j.psychres.2016.07.023 0165-1781/& 2016 Elsevier Ireland Ltd. All rights reserved.

evidence. Besides psycho-social-therapy (Orfanos et al., 2015), the other common modality of treatment that has been found to show significant improvement in negative symptoms and social functioning deficits, non-invasive brain stimulation methods like repetitive transcranial magnetic stimulation (rTMS) (Cole et al., 2015) and tDCS (Brunoni et al., 2014) have also been studied extensively. Treatment with rTMS has been suggested as a promising option in the management of positive, negative and cognitive symptoms of schizophrenia (Hovington et al., 2013). Gaebel and Zielasek (2015) remark treatment with rTMS as an ‘additional hope’ in the management of schizophrenia in the future. However, evidence based guidelines suggest, at best, ‘probable efficacy’ and ‘level B’ recommendation for the treatment of negative symptoms and ‘possible efficacy’ and ‘level C’ recommendation for the treatment of auditory hallucinations (Lefaucheur et al., 2014). The recommended paradigm and sites are – high frequency stimulation to the left dorso-lateral prefrontal cortex for negative symptoms and, low frequency stimulation to the left temporoparietal cortex for auditory hallucinations (Lefaucheur et al., 2014). Advent of novel stimulatory paradigms like theta burst stimulation (TBS)

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(Paulus, 2005) and theta range stimulation (Nongpiur et al., 2011) has revolutionalized the rTMS treatment strategies. While TBSrTMS to the conventional sites (i.e. left dorso-lateral prefrontal cortex for negative symptoms and left temporoparietal cortex for auditory hallucinations) have shown mixed results (Zhao et al., 2014; Koops et al., 2016), no study has so far used the theta range stimulation paradigm for treatment of schizophrenia. Moreover, there have been suggestions for the need for investigating alternate sites for stimulation in schizophrenia treatment, including the cerebellum (Freitas et al., 2009). While animal models have reported cellular and molecular responses to cerebellar rTMS (Morellini et al., 2015), human studies have demonstrated modulations in the cerebral default mode network and the cerebral dorsal attention system by delivering cerebellar rTMS (Halko et al., 2014). Cerebellar rTMS has also been shown to modulate language processing (Lesage et al., 2012). As the main role of cerebellum is motor functioning, cerebellar rTMS as a therapeutic option has been used mainly in movement disorders like cerebellar ataxia (Kim et al., 2014) and dyskinesias (Koch et al., 2009); lateral cerebellum is usually the target for stimulation. The study by Heath et al. (1979) was among the first to implicate the role of cerebellum in psychiatric disorders. Subsequently, several studies have suggested the role of cerebellum and its constituent functional and structural components in schizophrenia (for review see Andreasen and Pierson (2008), Picard et al. (2008) and Martin and Albers (1995)). Off late, several cerebellar molecular pathways applicable to schizophrenia have also been studied and identified (Yeganeh-Doost et al., 2011). Disturbed connections within multiple large-scale cerebellar functional networks have been implicated in patients with schizophrenia (Chen et al., 2013); supporting the ‘dysconnectivity hypothesis’, which proposes schizophrenia to be a disorder with dysconnectivity in the cortico-cerebellar-thalamic-cortical circuit (CCTCC). Interestingly, recent evidence suggests that these networks are affected in unaffected relatives of patients with schizophrenia as well (Guo et al., 2015). Using state-of-the-art neuroimaging metaanalysis, Bernard and Mittal (2015) demonstrated impaired cerebellar functional topography in schizophrenia patients. Among the constituent regions of the cerebellum, ‘vermis’ (esp. vermian-fastigial-forebrain pathways) has been specifically emphasized for its role in schizophrenia (Martin and Albers, 1995). Since Weinberger et al. (1979) reported cerebellar atrophy in schizophrenia, several other evidences have also accumulated. Some studies have found exclusive abnormality in the vermis (Ichimiya et al., 2001; Okugawa et al., 2003). Cerebellar vermal atrophy has been found to correlate significantly with general psychopathology, especially feelings of guilt and disturbance of volition (Sandyk et al., 1991); implying role in affective and motoric disturbances. Vermal atrophy has also been found to positively correlate with intellectual functioning (Nopoulos et al., 1999). Let apart chronic schizophrenia patients, studies on medication naïve first episode schizophrenia patients have also demonstrated structural vermal abnormalities that correlate with overall psychopathology, positive symptom sub-domain and cognitive cluster (Ichimiya et al., 2001; Okugawa et al., 2007). Therefore, cerebellar vermis can be a potential therapeutic target for the treatment of schizophrenia. However, trials pertaining to cerebellar stimulation in schizophrenia have been limited. Demirtas-Tatlidede et al. (2010) was the first and the only study so far to stimulate cerebellum using rTMS in treatment of schizophrenia. This study found significant improvement in negative symptoms and mood but did not show improvement in overall psychopathology; lack of a sham control group and meager sample size were the limitations. Therefore, in the present study, we performed a rater blind-

sham controlled randomized theta range rTMS to induce the excitability of cerebellar vermal cortex. We hypothesize that stimulation of cerebellar vermis will have significant improvements in positive, negative, mood symptoms and overall psychopathology in schizophrenia.

2. Methods 2.1. Subjects Patients meeting the diagnostic criteria for schizophrenia (using the Diagnostic Criteria for Research (DCR) of International Classification of Diseases – tenth edition (ICD-10)) (World Health organization, 1992) were approached; Diagnosis was made by a consultant psychiatrist or a senior resident after a detailed case work-up. Exclusion criteria included a prior history of a seizure not induced by drug withdrawal, patients receiving ECT (electroconvulsive therapy) in last 6 months, significant neurological illness or head trauma, significant unstable medical condition like uncontrolled hypertension, complicated diabetes mellitus, organ failures etc, left-handedness, current drug abuse, or inability to provide informed consent. Age range was 18–60. This investigation is the lead paper of the trial (Clinical Trials Registry India. no. CTRI/2015/03/005600). A total of 104 patients were screened between February to December 2012. A total of 47 patients were enrolled. All patients were inpatients and underwent regular physical examination, routine laboratory studies, ECG (electrocardiography). Patients were recruited after ‘initial stabilization’ (which was defined as since the day when patient becomes cooperative and amenable to various ward activities like morning group meetings, drug dispensing, and physical training drills) within a week of hospitalization (range: 3–6 days). Patients were required to remain on their psychotropic medication at same dosages for the duration of the trial. None of the patients were being provided any kind of individual psychotherapy. The study protocol was approved by the institute ethics committee and a signed, informed consent was obtained from every patient. Patients (n ¼47) were randomly allocated (using block randomization method) to rTMS and sham groups. The decision to enroll a patient was always made prior to randomization. Out of the 47 patients who were enrolled, 7 patients were not included in the final analysis (1- infective febrile illness; 1-severe extrapyramidal syndrome; 2- diagnosis revised to schizoaffective disorder; 3prematurely discharged); none of the 7 patients dropped out due to adverse effects of rTMS. Forty patients (20 in each group) completed the study (See Fig. 1 – chart showing patient flow in the study). The two groups were comparable in terms of age, gender, occupation, education, marital status, drug status, past and family history and indices of illness severity (Table 1). Patients were studied using a double-masked, parallel design i.e. study participants and clinical raters remained masked to allocated condition and parameters. 2.2. rTMS stimulation parameters A Magstim Rapids device (MAGSTIM Ltd., Whitland, Wales) and a double angled cone coil were utilized in the delivery of rTMS. Double-cone coils have been designed to stimulate deeperlying regions. The angle of the windings of this coil i.e. 135° and coils the diameter of their wings i.e. 90 mm differ from the routine ‘figure-of-eight’ coil that has an angle of 180° and wing diameter of 70 mm. Hardwick et al. (2014) compared stimulation of cerebellum by the double-cone coil with the figure-of-eight and the batwing coils, and found that the double-cone coil was the most

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cerebellum (MC) (Schutter et al., 2003). Both groups received a total of 10 rTMS sessions (5 days per week for 2 weeks). In active group, rTMS was applied at 5, 6, 7 Hz frequencies. Twenty pulses/train, 30 trains (10 trains each of 5, 6 and 7 Hz followed each other sequentially) with a total of 600 pulses. Train duration for 5 Hz stimulation was 4 s; for 6 Hz was 3.33 s; and for 7 Hz was 2.857 s and the inter-train interval was kept constant at 20 s. The theta range protocol for delivering high frequency i.e. excitatory rTMS was extrapolated from an excitatory priming paradigm used by studies on depression (Iyer et al., 2003; Nongpiur et al., 2011). This paradigm was specifically chosen to explore its role as a mode of high frequency stimulation in schizophrenia population. Excitatory rTMS was chosen to enhance cerebellar activity as it is considered to be a compensatory mechanism for dysfunctional cerebro-cerebellar circuitry in patients with schizophrenia (Andreasen et al., 1997; Kim et al., 2000; Potkin et al., 2002). The study by Demirtas-Tatlidede et al. (2010) studying cerebellar vermal rTMS in schizophrenia effectively used intermittent TBS, whose mechanism has been postulated to be excitatory as well. Total number of pulses delivered was chosen as 600 per session (for 10 sessions) because this particular regime has been shown to be safely tolerated in cerebellar rTMS (Demirtas-Tatlidede et al., 2010) and falls well within the safety guidelines as proposed by Wassermann (1998). The coil used in the present study was of

Fig. 1. Flow diagram showing participants' recruitment.

effective. Stimulation was administered at 100% resting motor threshold (RMT), which was ascertained prior to each stimulation session. Resting motor threshold was based on Rossini-Rothwell algorithm (Rothwell et al., 1999) defined as lowest intensity, which produced 5 MEP responses of at least 50 mV in 10 trials. The vermal part of cerebellum was stimulated at 1 cm below the ‘inion’ (the highest point of the external occipital protuberance) i.e. midline Table 1 Comparison of Socio-demographic and clinical variables between two Groups. Variable

Active N ¼ 20 n (%)

Sham N¼ 20 n (%)

χ2/t

df

P

Age (In years) Duration of illness (In years) Chlorpromazine equivalents (In g)

32.40 (8.44) 07.16 (7.49) 0.388 (0.110)

30.75 (7.90) 06.05 (5.60) 0.363 (0.129)

0.638 0.529 0.661

38 38 38

0.527 0.600 0.513

Sex

Male Female

17 (85) 03 (15)

16 (80) 04 (20)

0.173

1

1.000

Occupation

Employed Unemployed

07 (35) 13 (65)

09 (45) 11 (55)

0.417

1

0.519

Marital status

Married Unmarried

10 (50) 10 (50)

11 (55) 09 (45)

0.100

1

0.752

Habitat

Rural Suburban Urban

10 (50) 02 (10) 08 (40)

17 (80) 00 (00) 03 (15)

6.088

2

0.051

Drug Status

Typical antipsychotic Atypical antipsychotic Both

02 (10) 09 (45) 09 (45)

03 (15) 11 (55) 06 (30)

1.000

2

0.671

Past psychiatric history

Significant Not-significant

01 (05) 19 (95)

01 (05) 19 (95)

0.000

1

1.000

Religion

Hindu Others

18 (90) 02 (10)

16 (80) 04 (20)

0.784

1

0.661

Family psychiatric history

Significant Non-significant

08 (40) 12 (60)

07 (35) 13 (65)

0.107

1

0.744

Education

Illiterate Primary Secondary Graduation Post-Graduation/profession

04 02 09 04 01

03 02 10 05 00

1.307

4

1.000

(20) (10) (45) (20) (05)

(15) (10) (50) (25) (00)

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angled double-coned shape coil. This coil has the advantage of producing stronger stimulation (Lontis et al., 2006) of deeper brain areas (cerebellum) as compared to figure of 8 coil used in previous studies (Del Olmo et al., 2007; Minks et al., 2010). Sham rTMS stimulation was carried out by tilting the coil away from the scalp (45° from the scalp), so that both sound and scalp contact are roughly similar to those experienced during active stimulation. Similar method of sham stimulation has been used by previous studies (Goyal et al., 2007; McIntosh et al., 2004; Sandrini et al., 2011). Moreover, each patient was made to guess whether he is receiving active stimulation. 2.3. Clinical measures Clinical measures used in this study were composite positive and negative symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987), depressive symptoms using the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1990) and extrapyramidal side effects using Simpson-Angus Extrapyramidal Side Effects Scale (Simpson and Angus, 1970). PANSS sub (syndrome) scores – positive syndrome (PS), negative syndrome (NS), general psychopathology (GP) and total were assessed. The PANSS, CDSS and Simpson-Angus Extrapyramidal Side Effects Scale scores were assessed at baseline, after last session and at 4 weeks (2 weeks post-rTMS) by an independent rater to ascertain double-blinding.

educated till secondary level and were Hindus. None of the other variables were significantly different. Mean age of 32.40 78.44 years was observed in the active group while the sham control group had mean age of 30.757 7.90 years. The duration of illness was 7.16 77.49 years for the active group and 6.05 75.60 years for the sham group. Mean drug doses in terms of chlorpromazine (cpz) equivalents were not significantly different across the two groups. Mean cpz equivalent doses in active and sham groups were 388 mg and 363 mg respectively. The type of drug received also did not differ between the two groups. Haloperidol (4 patients in active group, 3 patients in sham group; dose range 5–10 mg), olanzapine (9 patients each in active and sham groups; dose range 10–15 mg), respiridone (5 patients in active group, 7 patients in sham group; dose range 2–04 mg) and quetiapine (2 patients in active group, 1 patient in sham group; dose range 100–200 mg). Resting motor threshold and power level did not reveal any significant difference (Mann Whitney U¼ 194.000; p ¼0.856) between the two groups. No significant between group difference was found on the number of guesses for active stimulation. 3.2. Safety and side effects There were no major side effects that are reported with high frequency rTMS stimulation (Tergau et al., 1997). Five patients reported transient headache responding to the analgesics. One patient reported excessive sleepiness after each session (side effect persisted for each session).

2.4. Statistical analysis

3.3. Outcome measures

Study data were analyzed using SPSS (Version 22). Statistical testing was two-sided with 5% as criterion for significance. The primary outcome variables were syndrome scores on the Positive and Negative Syndrome Scale. Secondary outcome measures were the CDSS and Simpson-Angus Extrapyramidal Side Effects Scale scores. The assumption of normality was verified by normal probability plots and the Kolmogorov-Smirnov test. The main analysis was the effect of treatment over time and group interaction between the active and sham groups in the double-blind phase. Group differences for sample characteristics were examined with independent t-test and chi-square test (wherever applicable). Motor threshold and power level between two groups were compared using Mann-Whitney U test. Overall effect of treatment over time for the two groups was analyzed using repeated measures analysis of variance with treatment (active/sham) as the between-subject factor and time (pre-treatment/after 10th session/2 wks Post rTMS Treatment) as the within-subject factor. To control for baseline differences, baseline scores were included as covariates. Bonferroni method for correction of multiple comparisons was applied for the analysis of PANSS data i.e. po 0.0125 (0.05/4 [syndrome scores]) was considered statistically significant. A complementary serial paired samples t test was also performed. Spearman correlation analysis was done between percentage reduction in various clinical scores and other significant clinicaldemographic variables.

At the baseline, while PANSS positive (t¼1.30;p ¼0.200) and negative syndrome (t¼ 1.67;p ¼0.103) and, CDSS scores (t ¼0.81; p¼ 0.421) were comparable, PANSS-general psychopathology (t¼ 2.47;p ¼ 0.018) and total scores (t ¼2.60;p ¼0.013) showed significant difference. However, when the Bonferroni correction was applied the difference on both variables lost statistical significance. Table 2 shows effect of time, group and time*group in the comparison of pre-post effects across the two groups. Repeated measures-ANOVA (with sphericity correction), found a significant group*time effect for PANSS-NS (F¼7.47; po 0.01), PANSS-Total (F¼4.05; po 0.05) and CDSS scores (F¼ 5.68; po 0.05). Significant effect of time, however, was found on all the scores. When baseline scores were included as covariates, while the significant group*time effect for PANSS-NS (F¼07.23; p o0.01) remained, PANSS-Total (F¼3.01; p ¼0.08) and CDSS scores (F¼2.78; p¼ 0.10) lost significance. Fig. 2a–c show differences over the treatment course in estimated marginal means of PANSS-NS, PANSS-total and CDSS scores across the two groups, respectively. Post hoc analyses reveal significant difference between the groups across pretreatment and after 10th session (p o0.001) in all the three scores. However, no significant difference, in any of the scores, was noted across both scores at after 10th session and 2 weeks post rTMS treatment. Reduction in the scores of PANSS-NS from baseline to after rTMS sessions (rho ¼ 0.55; p o0.05), and from baseline to 2 weeks post rTMS (rho ¼  0.50; p o0.05) in the active group showed significant negative correlation with baseline SAS scores. No significant correlations were observed.

3. Results 3.1. Sample characteristics

4. Discussion Table 1 shows comparison of socio-demographic variables between the active and sham group. Both groups had higher male representation, greater proportion were unemployed, belonged to lower socio-economic status and rural background; mostly

Our results showed that improvement in negative symptoms and depression symptoms over the course of treatment was significantly better in the group receiving active cerebellar vermal

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Table 2 Effect of Treatment across Active (rTMS) and Sham (Control) Groups over Time.

rTMS compared to those receiving sham sessions. Moreover, the improvement endured even till 2 weeks of treatment completion. This suggests that cerebellar vermal magnetic stimulation has significant effect on negative and affective symptoms in schizophrenia. This supports the study by Demirtas-Tatlidede et al. (2010) that suggested excitatory stimulation of cerebellar vermis to be effective in treating negative and mood symptoms. However, the effect sizes were smaller in the current study than the one by Demirtas-Tatlidede et al. (2010). This may be attributable to the inclusion of a sham comparative group, which is an advantage of the current study. 4.1. Effect on negative symptoms Meta-analyses have shown that high frequency-rTMS to left prefrontal cortex has been effective in alleviating negative symptoms in schizophrenia (Freitas et al., 2009; Dlabac-de Lange et al., 2010; Prikryl and Kucerova, 2013; Shi et al., 2014). However, when only sham-controlled studies were considered the effect sizes reduced. Moreover, a recent large-multicenter study reported that improvement by active application of high frequency rTMS to left prefrontal cortex was not significantly different than sham stimulation (Wobrock et al., 2015). In this context, positive evidence from the current study on the use of alternate protocols and sites of stimulation, like cerebellar vermis, might be valuable to the treatment of negative symptoms. 4.2. Effect on depressive symptoms Studies assessing the effect of transcranial magnetic stimulation at conventional sites on depressive symptoms in

schizophrenia show mixed results (Hajak et al., 2004; Jandl et al., 2005; Novák et al., 2006; Prikryl et al., 2007), with the study targeting cerebellar vermis showing significant improvement in depressive symptoms (Demirtas-Tatlidede et al., 2010). Certainly, significantly superior improvement in the active stimulation group compared to sham group in our study strongly propagates this novel treatment strategy in treating depressive symptoms in schizophrenia, apart from negative symptoms. However, the potential confound of the baseline difference in the scores suggests that patients having higher scores might improve better with active stimulation compared to sham. 4.3. What could be the reason for improvement in negative symptoms and mood in schizophrenia? Possible reasons of improvement might be due to neural network modulations brought by vermal rTMS. Koch (2010) proposed that high frequency rTMS stimulates lower threshold excitatory purkinje cells possibly resulting in indirect changes in dentate nucleus (deep cerebellar nuclei) excitability; and through synaptic relay in ventral thalamus, could induce variable modifications of the interneurons in cortical areas. These cortical interneurons possibly cause further excitation in areas of the frontal lobe implicated for negative symptoms (medial frontal areas) (Koutsouleris et al., 2008) and mood (anterior cingulated) (Fujimoto et al., 2007). Earlier we, in a case report, showed that cerebellar vermal high frequency rTMS increases frontal resting state EEG gamma power, suggesting that modulation of neuronal networks lead to activation in frontal regions resulting in the improvement in anergia and depression clusters in

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Fig. 2. a: Line chart showing the post hoc comparison of estimated measure of means of PANSS Negative Syndrome scores across the three time points between the active and the sham group. It shows the t/F and p values of serial paired t test, serial RANOVA (for two time points serially) along with the overall time and group effect. b: Line chart showing the post hoc comparison of estimated measure of means of PANSS Total scores across the three time points between the active and the sham group. It shows the t/F and p values of serial paired t test, serial RANOVA (for two time points serially) along with the overall time and group effect. c: Line chart showing the post hoc comparison of estimated measure of means of CDSS scores across the three time points between the active and the sham group. It shows the t/F and p values of serial paired t test, serial RANOVA (for two time points serially) along with the overall time and group effect.

schizophrenia (Garg et al., 2013). This hypothesis has been supported by PET studies; implicating a putative compensatory mechanism for dysfunctional cerebro-cerebellar circuitry in patients with hypo-frontal/negative symptoms (Kim et al., 2000).

Animal studies have shown that beneficial effects of rTMS in the treatment of negative symptoms are an outcome of underlying modulatory and enhancing effect on the mesolimbic dopaminergic systems (Keck et al., 2002). Similarly, its modulatory and

Fig. 3. The ‘Cerebellar rTMS differential neural modulation’ hypothesis.

S. Garg et al. / Psychiatry Research 243 (2016) 413–420

enhancing effect on the serotonergic systems, brought about by cortical interneurons, might explain the improvement in depressive symptoms. Here forth, we coalesce these findings from literature and propose a speculative “differential neural modulation hypothesis” (Fig. 3). High frequency rTMS to cerebellar vermis might induce variable modifications of the interneurons in cortical areas. These cortical interneurons might further cause excitation – in dorsolateral or medial prefrontal cortex areas (through dopaminergic neurotransmission) and in cingulate cortex (through serotonergic neurotransmission) bringing about improvement in negative symptoms and depressive symptoms. No significant effect on positive symptoms might suggest lack of effective neuronal connections with mesial temporal structures like amygdala, and hippocampus/parahippocampal region, which have been proposed as functional neuroanatomical correlates of positive symptoms (Goghari et al., 2010). 4.4. Limitations and strengths Generalizability of the findings is limited due to small sample size. Small effect sizes also confound the generalizability. Studies with larger sample sizes might provide better evidence. Gender proportion is skewed towards males, contributing to the limitation. The exclusion of drop-outs from the final analysis might be a limitation as there is a possibility that they might have been systematically different from those who did not. However, the fact that all these patients essentially required inpatient management (similar to those included in the analysis) and that the basis for dropping-out was not related to adverse effects of rTMS might provide a valid justification for dropping them from the analysis. Moreover, being the first rater blind sham controlled trial on cerebellar rTMS in schizophrenia, is the strength of the study. The stimulation paradigm chosen for the study (theta range) has been used in very sparse number of studies (those using priming stimulation); the mechanisms underlying this paradigm of stimulation might be unlike high the usual high frequency or the intermittent theta burst stimulation. Lack of experimental studies investigating this paradigm might limit the generalization of the inferences. There is a certain need of experimental studies that compare this paradigm with other more commonly used excitatory stimulation paradigms. Use of the method for sham stimulation (i.e. 45° tilt) has been suggested ‘not to be devoid of action on brain’ and is a significant limitation. The lack of significant time*group effect on some variables assessed or significant effect of time in the sham group might be attributable to this. Future studies should use sham coils instead or use a cross over design that has been proposed to have a lesser placebo effect while using ‘tilt’ method for sham stimulation (Dollfus et al., 2016). Finally, although the hypothesis proposed for ‘the reason for improvement in negative symptoms and mood in schizophrenia’ was based on the positive findings from the study and some earlier evidences, it is a speculative one and needs to be pragmatically studied in future molecular experimental paradigms. 4.5. Conclusion There is significant improvement in negative symptoms and depressive symptoms in schizophrenia when high frequency magnetic stimulation was delivered to cerebellar vermis. With respect to depressive symptoms, there is also a suggestion that patients having higher scores improve better with active stimulation compared to sham. Additionally, we also conclude that this mode of stimulation might not be effective in treating positive symptoms. Hence, cerebellar stimulation can be used as an

419

effective adjunct to pharmacological agents in treating intricate and lingering negative and affective symptoms.

Conflict of interest There are no conflicts of interest.

Financial disclosures The authors have not received any form of financial support to carry out this work and report no competing interests relevant to this work.

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