Memory changes following adjuvant temporo-parietal repetitive transcranial magnetic stimulation in schizophrenia.

OBJECTIVE: The use of repetitive transcranial magnetic stimulation (rTMS) in schizophrenia has shown improvement as well as deficits in memory. Though most studies had focused on dorsolateral prefrontal cortex only, but impact of rTMS on cognitive functions remain inconclusive. The need of the study is to assess the impact of rTMS on memory in schizophrenia.
MATERIALS AND METHODS: Forty right-handed male patients with schizophrenia were included by purposive sampling and rated on Positive and Negative Syndrome Scale (PANSS) before starting the rTMS treatment with the experimental group. Low frequency 1 Hz rTMS including 1200 stimulations were given over temporo-parietal cortex for 20 min as add on to medications. At the end of 10 session treatment (5 days a week for 2 weeks), the patients were re-evaluated.
RESULTS: A total of 39 patients (20 for experimental group and 19 for control group) with mean age of 29.70 ± 9.05 and 31.26 ± 7.78 years, respectively, shows significant difference to pre- and post-treatment mean PANSS score in positive, negative and general psychopathology domains. The pre- and post-treatment mean Postgraduate Institute Memory Scale Scores with multivariate repeated measures analysis of variance revealed significant improvements in all memory domains (P < 0.01) except remote memory in both experimental and control groups.
CONCLUSION: RTMS in combination with antipsychotics has shown improvement in psychopathology in patients of schizophrenia without any deterioration of memory. Copyright:

INTRODUCTION

Cognitive deficits are one of the important factors which predict long-term outcomes in persons with schizophrenia. Specific cognitive deficits incorporates working and episodic memory, attention, language comprehension, processing speed, and executive function.[1] Apparently patients with schizophrenia might be differing with healthy control on functional integrity, organization, and activation of neuronal networks responsible for various cognitive functioning and memory.[2] Repetitive transcranial magnetic stimulation (rTMS) can be used to modulate specific brain areas, which is found to be beneficial for various neuropsychiatric conditions.[3] While with rTMS, several additional safety studies have not reported any adverse sustained changes in cognitive function,[45] some studies have shown improvement in verbal memory and motor reaction times,[56] decrease in the latency for picture naming.[5] However, there are reports of worsening of immediate and delayed recall.[6] The dorsolateral prefrontal cortex, left temporo-parietal areas and parietal stimulation by rTMS influences working memory by improving,[7] or may cause deterioration.[8] These functions could be verbal working memory performance,[9] or visual working memory performance.[10] Since most of these studies have been carried out in healthy, young adults, we undertook the current study to find out the effects of adjuvant left temporo-parietal rTMS on memory functions in patients with schizophrenia; with proposed null hypothesis of no effects of adjuvant rTMS on memory functions among patients of schizophrenia.

MATERIALS AND METHODS

This study was conducted at a tertiary care psychiatric institute by department of psychiatry and department of clinical psychology. The study protocol was approved by the institutional review board of the institute.

Forty male schizophrenia patients recruited through purposive sampling, aged between 18 and 50 years were assigned into experimental (n = 21) and control groups (n = 19) by group allocation. One patient of experimental group was prematurely discharged before completion of study, hence dropped from the study. Right handedness was assessed using Handedness Preference Schedule.[11] Those with comorbid psychiatric or neurological disorder, having metallic implants in body or treated with electroconvulsive therapy in past 6 months were excluded from the study. Patients were then rated on Positive and Negative Syndrome Scale (PANSS)[12] and Postgraduate Institute Memory Scale (PGI-MS).[13] PGI-MS is a structured verbal test standardized for Indian population. It includes tests of various domains such as attention and concentration, recent and remote memory, delayed and immediate recall, recognition of common objects, verbal retention of similar and dissimilar pairs and mental balance. Experimental group received a total of 10 rTMS sessions (5 days per week for 2 weeks) in addition to medication and after the session at day-11, a reassessment using PANSS and PGI-MS was done. Control group was not given any rTMS session but was assessed twice with the same tools before and after 2 weeks interval. All the medications that the patient received during this period were decided primarily by the treating team and the investigators were blind to it.

Motor threshold estimation

Neuropack Sigma evoked potential measuring system (Nihon Kohden, Japan) was used. The MT for the right abductor pollicis brevis was decided using a figure of eight shaped coil at 1 Hz frequency as per Rossini-Rothwell algorithm.

Stimulation procedure

Left sided 1-Hz stimulation in experimental group was provided over temporoparietal region using Magstim Rapid magnetic stimulator (Magstim Company Ltd, Whiteland, UK) with figure of eight coil in one continuous, 20 min train at 100% of the resting motor threshold delivering 1200 stimulations.

The results obtained were analyzed using the computer software program Statistical Package for Social Sciences (SPSS)-version 10.0 (SPSS for Windows, Version 10.0. Chicago, IL, SPSS Inc.). Description of sample characteristics was done with descriptive statistics-mean and standard deviation. Group differences for continuous sample characteristics were evaluated with independent t-test. To compare the overall impact of intervention over treatment time period for the two groups, a set of multivariate repeated measures analysis of variance was employed with treatment/intervention as the between-group factor and time as the within-group factor.

RESULTS

A total of 39 patients (20 for experimental group and 19 for control group) were included for the study. Table 1 summarizes the sample characteristics with group difference. The mean age of the experimental group was 29.70 ± 9.05 years and it was 31.26 ± 7.78 for control group (t = −0.577, df = 37, P = 0.567). Similarly, across the variables of years of education, duration of illness, age of onset, duration of present episode and chlorpromazine equivalent antipsychotic dose, there was no significant group difference was found. There was significant difference in between pre- and post-treatment mean PANSS scores for both the groups [Table 1].

Table 1

Comparison of clinical variables between experimental (n=20) and control groups (n=19) and pre-post repetitive transcranial magnetic stimulation mean positive and negative syndrome scale score difference

Variables	Mean±SD		t	df	P
	Experimental (n=20)	Control (n=19)
Age (years)	29.70±9.05	31.26±7.78	-0.577	37	0.567
Years of education	9.65±3.73	10.89±2.51	-1.22	37	0.232
Duration of illness	4.85±5.68	4.47±3.39	-0.250	37	0.804
Age of onset (years)	24.80±6.89	26.84±7.43	-0.891	37	0.379
Duration episode	3.44±3.34	4.01±3.72	-0.509	37	0.613
Treatment (chlorpromazine equivalent/day)	499.77±231.52	404.06±181.39	1.455	37	0.154
PANSS scores	Mean±SD		F		P
	Experimental (n=20)	Control (n=19)
Prepositive	25.45±3.44	24.26±2.81	18.184		<0.001**
Postpositive	14.40±5.24	19.57±3.49
Prenegative	23.45±5.02	21.63±4.65	10.505		0.003*
Postnegative	15.50±5.55	18.52±4.34
Pre-Gen Psy-path	39.20±5.92	38.63±4.65	7.953		0.008*
Post-Gen Psy-path	25.65±5.29	32.26±5.41
Pretotal	88.60±9.73	84.52±9.99	11.588		0.002*
Posttotal	55.55±13.99	67.21±18.38

*P<0.01 (two-tailed), **P<0.001 (two-tailed). PANSS – Positive and negative syndrome scale; SD – Standard deviation

The mean PGI-MS Scores were assessed pre- and post-treatment and compared, with treatment there was significant improvements in all memory domains (P < 0.01) of PGIMS except remote memory in both experimental and control groups [Table 2]. None of the patients of experimental group developed any side effects of rTMS during study period.

Table 2

Effect of treatment across experimental and control groups over time: Postgraduate institute memory scale scores within subjects (n=39)

Variables	Mean±SD		F	P
	Pre t/t	Post t/t
Remote
Exp	4.00±1.59	4.05±1.57	0.000	0.994
Ctrl	4.37±1.06	4.32±1.00
Recent
Exp	4.05±1.23	4.75±0.64	15.186	<0.001**
Ctrl	4.16±0.76	4.74±0.56
Mental balance
Exp	5.85±2.08	6.50±2.09	12.185	0.001*
Ctrl	5.42±2.09	6.42±2.23
Attention conc
Exp	6.90±2.36	7.65±2.18	23.983	<0.001**
Ctrl	7.42±1.68	7.94±1.68
Delayed recall
Exp	5.80±3.00	6.45±2.24	9.432	0.004*
Ctrl	6.10±2.07	7.74±1.33
Immediate recall
Exp	5.15±2.35	5.90±2.47	8.599	0.006*
Ctrl	6.68±3.02	7.53±2.25
Retention for similar pairs
Exp	3.30±1.38	4.25±1.29	32.211	<0.001**
Ctrl	2.63±1.61	4.21±0.79
Retention for dissimilar pairs
Exp	7.02±2.77	7.95±2.91	20.842	<0.001**
Ctrl	6.37±2.73	8.37±1.83
Visual memory
Exp	5.95±3.56	7.65±2.87	36.398	<0.001**
Ctrl	6.31±2.79	8.21±2.57
Recognition
Exp	6.73±2.41	8.25±1.92	50.808	<0.001**
Ctrl	6.92±2.39	8.53±1.43

*P<0.01 (two-tailed); **P<0.001 (two-tailed). Exp – Experimental group; Ctrl – Control group; SD – Standard deviation

DISCUSSION

This study intended to assess impact of rTMS on the left temporo-parietal region on cognitive functions such as executive and memory functioning and psychopathology among patients of schizophrenia. There was equally and significant improvement of most of the cognitive functions (except for remote memory) in both experimental and control group. However, there was significant improvement in both experimental and control group as pre- to post-PANSS score; but most importantly posttreatment mean PANSS score of experimental group was significantly lower than control group. This can be implicated for favoring adjunctive use of rTMS for better and faster response in schizophrenia. This beneficial effects is in accordance to a study in which low frequency rTMS over temporo-parietal region was used for the treatment of auditory hallucinations in recent onset schizophrenia[14] and other similar studies.[1516]

In our study, rTMS stimulation were provided over temporo-parietal region with a slow rate (1 Hz), against other studies examining rTMS in schizophrenia, in which, to assess the cognitive functioning, rapid rate stimulation was given primarily over dorsolateral prefrontal region.[1718] Low frequency stimulation of tempero-parietal region was used in this study in accordance with the existing evidence for treating psychosis having auditory verbal hallucinations as a prominent symptoms.[19] The fronto-temporal-limbic dysfunction hypothesis, is based on functional imaging studies and many other studies.[2021] It attributes disconnection of hippocampus with prefrontal cortical areas for neuropsychological dysfunction in schizophrenia.

Delivering low frequency rTMS over the ipsilateral parietal lobe prior to task execution, results into improvement in attention to a visual task.[22] The present study findings are similar to studies which have investigated the effect of rTMS on various cognitive functions especially memory in disorders like depression and schizophrenia.[23] It ought to likewise be noticed that despite improvement in task performance presented by most of the patients, they remained within dysfunction limit, strengthening the notion that there are continuing cognitive deficits in association with psychosis.[24] Thus impairment in cognition is a reflection of a supposedly more deteriorative course in schizophrenia.

The role of antipsychotics cannot be excluded in beneficial effects of rTMS, it is conceivable that the absence of significant differences in direct comparison between the two groups could be an outcome of the generally modest sample size prompting a Type II error. Still, we can conclude that rTMS in combination with antipsychotics has shown statistically significant clinical effect on the treatment of psychopathology without any deterioration of memory. This positive effect on memory further taken as good effect of rTMS in schizophrenia.

Limitation includes lack of sham rTMS in control group, sample consisted of male patients only, continuation of conventional pharmacotherapy and doses is a major confounding factor in the interpretation of results. Due to low and short stimulation parameters there may be absence of evidence for cognitive deterioration, hence in future larger sample size with longer duration of rTMS treatment should be considered.

CONCLUSION

We observed no adverse effect of rTMS on memory functioning, but significant positive effect of rTMS on psychopathology of schizophrenia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.