Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia.
BACKGROUND
Early invasive electrical stimulation studies suggested that enhancement of cerebellar vermal activity might prove valuable in symptomatic treatment of refractory neuropsychiatric diseases via modulation of emotion and affect. This proof of principle study aimed to test this hypothesis using noninvasive brain stimulation, and to explore the safety of this protocol in schizophrenia.


METHODS
Eight treatment-refractory patients with schizophrenia underwent ten sessions of intermittent theta burst stimulation (TBS) to the cerebellar vermis using MRI-guided transcranial magnetic stimulation (TMS). Assessments included side effect questionnaires, cardiovascular monitoring, psychiatric evaluations and comprehensive neuropsychological testing before and after TBS and at one-week follow-up.


RESULTS
Overall, TBS was tolerated well with mild side effects primarily comprising neck pain and headache. No serious adverse events occurred. Diastolic blood pressure (BP) showed mild decreases for five minutes post-TBS; no significant changes were detected for systolic BP or pulse. PANSS negative subscale showed significant improvements following TBS and during the follow-up. Calgary Depression Scale and self-report visual analog scales for Happiness and Sadness pointed to significant mood elevation. Neuropsychological testing revealed significantly fewer omissions in working memory and interference conditions of a Continuous Performance Test, a longer spatial span and better delay organization on the Rey-Osterrieth Complex Figure during follow-up. No significant worsening in psychiatric or neuropsychological measures was detected.


CONCLUSIONS
Theta burst stimulation of the cerebellar vermis is safe and well-tolerated, while offering the potential to modulate affect, emotion and cognition in schizophrenia. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.
Demirtas-Tatlidede
Asli
A
Harvard Medical School, Boston, MA, United States.
Freitas
Catarina
C
Cromer
Jennifer R
JR
Safar
Laura
L
Ongur
Dost
D
Stone
William S
WS
Seidman
Larry J
LJ
Schmahmann
Jeremy D
JD
Pascual-Leone
Alvaro
A
D000328:Adult; D001794:Blood Pressure; D002531:Cerebellum / Q000503:physiopathology*; D003071:Cognition; D004644:Emotions; D005260:Female; D005500:Follow-Up Studies; D006240:Happiness; D006261:Headache / Q000209:etiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D008875:Middle Aged; D019547:Neck Pain / Q000209:etiology; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D012565:Schizophrenic Psychology; D013826:Theta Rhythm; D050781:Transcranial Magnetic Stimulation / Q000009:adverse effects / Q000379:methods; D016896:Treatment Outcome
Am J Psychiatry. 2000 Apr;157(4):542-8
10739412
Am J Psychiatry. 1999 Jul;156(7):1105-7
10401463
Cerebellum. 2005;4(2):123-7
16035194
Am J Psychiatry. 2003 Sep;160(9):1614-7
12944335
Am J Psychiatry. 2005 Jun;162(6):1203-5
15930071
Clin Neuropathol. 1999 Jul-Aug;18(4):198-204
10442462
Arch Neurol. 1991 Nov;48(11):1178-87
1953406
Biol Psychiatry. 2001 Jan 1;49(1):20-7
11163776
J Neurophysiol. 2007 Jul;98(1):145-52
17460103
Br J Psychol. 1970 Aug;61(3):303-21
5457503
Lancet. 1997 Jun 14;349(9067):1730-4
9193383
Brain Res. 1975 Sep 23;95(2-3):423-42
1156883
Psychiatry Res. 2008 Aug 30;163(3):193-200
18656332
J Neurophysiol. 1959 Jul;22(4):451-7
13673296
Biol Psychiatry. 2008 Mar 1;63(5):519-23
17662964
Schizophr Res. 1994 May;12(2):183-4
8043529
Biol Psychiatry. 2000 Nov 15;48(10):962-70
11082469
J Neuropsychiatry Clin Neurosci. 2004 Fall;16(4):400-8
15616166
Neurosci Biobehav Rev. 1982 Spring;6(1):47-53
7041016
Cortex. 2010 Jul-Aug;46(7):831-44
20152963
Schizophr Res. 2002 May 1;55(1-2):61-7
11955964
Brain Res. 1978 Sep 22;153(2):241-61
80249
Arch Neurol. 1976 Aug;33(8):559-70
821458
Am J Psychiatry. 1983 Oct;140(10):1322-6
6624962
Neurology. 2009 Jul 14;73(2):113-9
19597133
Clin Neurophysiol. 2008 Nov;119(11):2559-69
18824403
Hum Brain Mapp. 1996;4(3):174-98
20408197
Neuroscience. 1976 Jun;1(3):205-17
11370232
Lancet Neurol. 2003 Mar;2(3):145-56
12849236
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9985-90
8790444
Neuroimage. 2008 Mar 1;40(1):265-74
18226550
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83
17170134
J Nerv Ment Dis. 1977 Nov;165(5):300-17
303280
Brain. 1998 Apr;121 ( Pt 4):561-79
9577385
Cerebellum. 2007;6(3):254-67
17786822
Lancet. 1996 Jul 27;348(9022):233-7
8684201
Neuropsychobiology. 2004;50(2):119-23
15292664
Am J Psychiatry. 2002 Feb;159(2):227-37
11823264
Neurosci Lett. 2009 Oct 16;464(1):18-21
19682544
Eur J Neurol. 2010 Feb;17(2):295-300
19863647
J Neuropsychiatry Clin Neurosci. 2005 Spring;17(2):260-2
15939990
Brain. 2007 Oct;130(Pt 10):2646-60
17872929
Biol Psychiatry. 1978 Oct;13(5):501-29
728506
Neuron. 2005 Jan 20;45(2):201-6
15664172
Clin Neurophysiol. 2009 Dec;120(12):2008-2039
19833552
Int J Neurosci. 1993 Jul-Aug;71(1-4):1-7
8407138
Science. 1973 Nov 23;182(4114):845-7
4795751
J Neurol Neurosurg Psychiatry. 1969 Apr;32(2):82-7
5783297
Neurosci Lett. 2003 Jan 16;336(2):73-6
12499043
Eur Neurol. 1999;41(3):150-2
10202246
Neuroimage. 2009 Jan 15;44(2):489-501
18835452
Neurosci Lett. 2006 Apr 24;397(3):229-33
16426754
Int J Neuropsychopharmacol. 2010 Apr;13(3):387-93
20128955
Schizophr Res. 2007 Jul;93(1-3):79-89
17383859
Schizophr Res. 2005 Nov 15;79(2-3):231-8
15982856
Schizophr Bull. 1998;24(2):203-18
9613621
Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 30;30(8):1408-12
16844275
Am J Psychiatry. 2005 Apr;162(4):790-2
15800155
Am J Psychiatry. 2001 Jun;158(6):952-4
11384906
Cerebellum. 2009 Mar;8(1):52-60
18972181
Am J Psychiatry. 1998 Sep;155(9):1288-90
9734558
Psychiatry Res. 2001 Oct 1;107(3):125-34
11566429
Lancet. 1979 Mar 31;1(8118):718-9
85950
Arch Gen Psychiatry. 1997 Feb;54(2):159-65
9040284
Biol Psychiatry. 1999 Sep 1;46(5):703-11
10472423
Biol Psychiatry. 2009 May 1;65(9):778-84
19070834
J Neurosci Res. 1976;2(2):133-46
950678
Neuroimage. 1999 Sep;10(3 Pt 1):233-60
10458940
Neurosci Res. 1991 Oct;12(1):45-56
1660994
J Psychiatr Res. 2007 Oct;41(8):645-51
16626741
Neuroscience. 2001;105(1):219-29
11483314
Brain. 2010 May;133(Pt 5):1505-14
20350936
Clin Neurophysiol. 2010 May;121(5):802
20153250
Schizophr Res. 2009 Jun;111(1-3):196-7
19339158
Lancet. 1981 Sep 26;2(8248):700-1
6116081
Trends Cogn Sci. 1998 Sep 1;2(9):362-71
21227233
Neuropsychology. 1998 Oct;12(4):505-18
9805320
Schizophr Bull. 2006 Apr;32(2):225-30
16469940
Int Rev Neurobiol. 1997;41:3-27
9378594