Schizophrenia Research 143 (2013) 225–227

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Schizophrenia Research

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Letter to the Editor

Amelioration of anergia and thought disorder with adjunctivehigh frequency cerebellar vermal repetitive transcranialmagnetic stimulation in schizophrenia: A case report

Dear Editor,

In recent times, repetitive transcranial magnetic stimulation(rTMS) has emerged as a new therapeutic option in patients withschizophrenia showing treatment resistance, which is about 10–30%of the total schizophrenia population (Conley and Buchanan, 1997).Preferred site of stimulation for positive symptoms in schizophreniais temporo-parietal region and for negative symptoms is dorso-lateral pre-frontal cortex. However, stimulation of these sites hasbeen shown to have moderate to insignificant effect on positive andnegative symptoms respectively (Slotema et al., 2010). As cerebellumand its abnormalities have been implicated in positive symptomsalong with negative symptoms and impaired cognitive processes inschizophrenia, stimulation of this alternate site has been suggestedas a novel target for treating patients with this disorder (Freitas etal., 2009). Hardly there are any systematic trials on therapeutic effectof rTMS on cerebellum in schizophrenia. We report a case of firstepisode schizophrenia, which showed improvement in anergia andthought disorder after receiving high frequency cerebellar vermalrTMS.

Mrs. S.M, a 42 year old right-handed, Hindu, married female had2 years of continuous illness characterized by reduced interactions,irrelevant talk, fearfulness, muttering behavior and suspiciousness.Patient on mental status examination had hallucinatory behavior,with incoherent and irrelevant speech, and loosening of association.Patient was diagnosed as schizophrenia, undifferentiated type as perDCR of ICD-10. Patient was neuroleptic naïve. Baseline investigationsincluding hematology, biochemistry, endocrinology and CT scan ofbrain were unremarkable. After receiving risperidone in a dose of6 mg per day for 6 weeks, she showed only minimal improvementin symptomatology especially in formal thought disorder and thenegative symptoms.

Baseline and subsequent severity rating using Positive and NegativeSymptom Scale (PANSS) was performed by SKT who was blind to thetreatment protocol. Cluster scores were obtained from PANSS— Anergia(N1+N2+G7+G10), Thought disturbance (P2+P3+P5+G9), acti-vation (P4+G4+G5), paranoid/belligerence (P6+P7+G8) and de-pression (G1+G2+G3+G6). A baseline (i.e. one day prior tothe start of rTMS sessions) and post rTMS (i.e. one day after thelast rTMS session) EEG was recorded using a custom-made scalp capwith 192 Ag–Ag/Cl electrodes placed according to the international10-5 system. Electrode impedance was kept b5 kΩ. EEG was filtered(time constant — 0.1 s, high frequency filter — 120 Hz) and digitized(sampling rate — 512 Hz, 16 bits) using Neurofax EEG-1100K. Firstsixty-second epochs of artifact-free EEG data were visually selectedand recomputed against common average reference. Spectral power,expressed in μV, (fast Fourier transform routine, Hamming window)

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was calculated usingWelch's averaged periodogrammethod. Frequen-cies between 30 and 50 Hz were analyzed and spectral power wasaveraged region-wise (right and left frontal, parietal, temporal andoccipital). Matlab 6.5 version was used for EEG analysis.

Resting motor threshold (MT) was calculated using a figure-of-eight shaped coil with a diameter of 70 mm (Magstim Inc., Whitland,UK) as per Rossini–Rothwell algorithm. rTMS stimulation was givento vermal part i.e. midline cerebellum (MC) at a site 1 cm below theinion (Iz, 10–20 international system) using double angled shapecoil. Patient was given 20 trains of 30 pulses each; in the thetafrequency range (5 Hz for the first 7 trains, 6 Hz for the next 7 trainsand 7 Hz for the rest 6 trains) to a total of 600 pulses at 100% MT. Atotal of 10 sessions over the period of 2 weeks were given. Medica-tions remained unchanged and patient did not report any side effectsafter receiving rTMS.

PANSS total score at baseline was 78 which decreased to 40,measured at 2nd week post rTMS. Anergia scores reduced from 17at baseline to 6 at completion of rTMS sessions and thought distur-bance scores reduced from 17 to 7. Other scores did not show muchdifference. These scores were maintained at 4th and 6th weeks aswell. Post rTMS EEG showed significant increase in the left frontal(pre, −0.911; post, 1.934; mean difference, −2.845), right frontal(pre, −0.723; post, 1.786; mean difference, −2.509) and left occipi-tal (pre, 0.047; post, 1.066; mean difference, −1.019) regions. Signif-icant reduction in spectral power was seen in left temporal region(pre, 0.868; post, −1.141; mean difference, 2.011). Spectral powerin the other regions did not differ significantly. Spectral maps inFig. 1 represent these findings.

A lower or only a moderate success rate of rTMS has been attributedto the selection of patients with treatment resistance (Slotema et al.,2010). This case study was an attempt to add rTMS as an adjunct toantipsychotics early in the course of treatment and observe its effects.Additionally, considering the role of cerebellum in cognition, affectand psychosis (Tavano et al., 2007), significant association betweensymptoms of schizophrenia and vermal while matter volume (Levittet al., 1999; Greenstein et al., 2011) and expression of various geneticmarkers of schizophrenia being altered in cerebellum (Villanueva, inpress),we chose cerebellar vermal site for rTMS. Furthermore, intermit-tent Theta Burst Stimulation (iTBS) over vermal cerebellar region is doc-umented to be safe in refractory schizophrenia (Demirtas-Tatlidedeet al., 2010). For similar reasons we used high frequency rTMS. Wechose 30–50 Hz frequency band for analysis because recent studieshave demonstrated the modulatory role of rTMS can gamma (30–50 Hz) oscillatory activity (Barr et al., 2011).

The index patient showed significant improvement in anergia(65%) and thought disturbance (60%) at completion of rTMS ses-sions and this improvement persisted over time. There are otherstudies that found similar improvements in patients of schizophre-nia with cerebellar rTMS (Demirtas-Tatlidede et al., 2010). Possiblereasons of improvement might be neural network modulationsbrought by vermal rTMS. High frequency rTMS has been proposedto stimulate lower threshold excitatory Purkinje cells resultingin indirect changes in dentate nucleus excitability and induce

Fig. 1. [a] Shows the region wise arrangement of 192 channels; [b] and [c] show the distribution of spectral power in 30–50 Hz frequency range across various brain areas. Signif-icant differences are noted in bilateral frontal (post>pre), left temporal (postbpre) and left occipital (post>pre) regions.

226 Letter to the Editor

variable modifications of the interneurons in cortical areas causingexcitation in fronto-temporal areas through synaptic relay in ven-tral thalamus (Koch, 2010). Moreover, change in the gamma spec-tral power post rTMS i.e. increase in bilateral frontal regions(findings supported by Schutter et al., 2003) and reduction in lefttemporal spectral power in the patient also support this hypothe-sis. Role of frontal cortex in negative symptoms and left temporalcortex in thought disorder (Heimer et al., 1997; McGuire et al.,1998) in schizophrenia is rather well known. Also, PET studieshave shown that increased cerebellar activity is more of a compen-satory mechanism for dysfunctional cerebro-cerebellar circuitry inpatients with hypofrontal/negative symptoms (Kim et al., 2000;Potkin et al., 2002). Improvement in other clusters i.e. activation,paranoid and depression (35 to 45%) also can be explained withthese possible reasons. So we conclude that cerebellar vermalhigh frequency rTMS might modulate neuronal networks causingactivation in frontal regions resulting in the improvement inanergia and the inhibition in temporal regions resulting in the im-provement of thought disturbance. This report suggests a need toconduct systematic randomized sham controlled trials to investi-gate the efficacy of high frequency cerebellar rTMS on symptom-atology in schizophrenia.

References

Barr, M.S., Farzan, F., Arenovich, T., Chen, R., Fitzgerald, P.B., Daskalakis, Z.J., 2011. Theeffect of repetitive transcranial magnetic stimulation on gamma oscillatory activityin schizophrenia. PLoS One 6, e22627.

Conley, R.R., Buchanan, R.W., 1997. Evaluation of treatment-resistant schizophrenia.Schizophr. Bull. 23, 663–674.

Demirtas-Tatlidede, A., Freitas, C., Cromer, J.R., Safar, L., Ongur, D., Stone, W.S., Seidman,L.J., Schmahmann, J.D., Pascual-Leone, A., 2010. Safety and proof of principle studyof cerebellar vermal theta burst stimulation in refractory schizophrenia. Schizophr.Res. 124, 91–100.

Freitas, C., Fregni, F., Pascual-Leone, A., 2009. Meta-analysis of the effects of repetitivetranscranial magnetic stimulation (rTMS) on negative and positive symptoms inschizophrenia. Schizophr. Res. 108, 11–14.

Greenstein, D., Lenroot, R., Clausen, L., Chavez, A., Vaituzis, A.C., Tran, L., Gogtay, N.,Rapoport, J., 2011. Cerebellar development in childhood onset schizophrenia andnon-psychotic siblings. Psychiatry Res. 193, 131–137.

Heimer, L., Harlan, R.E., Alheid, G.F., Garcia, M.M., de Olmos, J., 1997. Substantia innominata:a notion which impedes clinical-anatomical correlations in neuropsychiatric disorders.Neuroscience 76, 957–1006.

Kim, J.J., Mohamed, S., Andreasen, N.C., O'Leary, D.S., Watkins, G.L., Boles Ponto,L.L., Hichwa, R.D., 2000. Regional neural dysfunctions in chronic schizo-phrenia studied with positron emission tomography. Am. J. Psychiatry 157,542–548.

Koch, G., 2010. Repetitive transcranial magnetic stimulation: a tool for human cerebellarplasticity. Funct. Neurol. 25, 159–163.

Levitt, J.J., McCarley, R.W., Nestor, P.G., Petrescu, C., Donnino, R., Hirayasu, Y., Kikinis, R.,Jolesz, F.A., Shenton, M.E., 1999. Quantitative volumetric MRI study of the cerebellum

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and vermis in schizophrenia: clinical and cognitive correlates. Am. J. Psychiatry 156,1105–1107.

McGuire, P.K., Quested, D.J., Spence, S.A., Murray, R.M., Frith, C.D., Liddle, P.F., 1998.Pathophysiology of ‘positive’ thought disorder in schizophrenia. Br. J. Psychiatry173, 231–235.

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Schutter, D.J., van Honk, J., d'Alfonso, A.A., Peper, J.S., Panksepp, J., 2003. High frequencyrepetitive transcranial magnetic over themedial cerebellum induces a shift in the pre-frontal electroencephalography gamma spectrum: a pilot study in humans. Neurosci.Lett. 336, 73–76.

Slotema, C.W., Blom, J.D., Hoek, H.W., Sommer, I.E.C., 2010. Should we expand the toolbox of psychiatry treatment methods to include repetitive transcranial magneticstimulation (rTMS)? A metaanalysis of the rTMS in psychiatric disorders. J. Clin.Psychiatry 71, 873–884.

Tavano, A., Grasso, R., Gagliardi, C., Triulzi, F., Bresolin, N., Fabbro, F., Borgatti, R., 2007.Disorders of cognitive and affective development in cerebellar malformations.Brain 130, 2646–2660.

Villanueva, R., 2012. The cerebellum and neuropsychiatric disorders. Psychiatry Res.198, 527–532 http://dx.doi.org/10.1016/j.psychres.2012.02.023.

Shobit GargSai Krishna Tikka⁎

Nishant GoyalVinod Kumar Sinha

Shamsul Haque NizamieCentre for Cognitive Neurosciences & Department of Psychiatry, Central

Institute of Psychiatry, Kanke, Ranchi 834006, Jharkhand, India⁎Corresponding author. Tel.: +91 8298041330;

fax: +91 96512233668.E-mail address: cricsai@gmail.com (S.K. Tikka).

12 August 2012