NEUROIMAGING CENTER
Brain Imaging Center
LFMS: Low Field Magnetic Stimulation
Original EP-MRSI Study in Volunteers with Bipolar Disorder
Full report has been published in the American Journal of Psychiatry, January 1 2004 (abstract)
EP-MRSI Study in Humans
In the EP-MRSI study, several populations of subjects with bipolar disorder received EP-MRSI exams over multiple visits, often with changes in medication occurring throughout the study. After several subjects finished the EP-MRSI exam with obvious mood improvement, a structured mood rating scale called the Brief Affect Scale (BAS) was added to the study and administered immediately before and after the EP-MRSI exam. Comparison groups of normal subjects were recruited to receive EP-MRSI exams, and subjects with bipolar disorder were recruited to receive sham EP-MRSI exams. The sham EP-MRSI exam was a standard structural MRI exam that did not contain the EP-MRSI scans.
Clinical Methods The study population was comprised of participants in three studies of subjects with bipolar disorder who shared the same EP-MRSI scan prescription and clinical interview scheme. These studies were investigating the effects of conventional and non-conventional (omega3 fatty acid supplements) therapies on mood and brain chemistry over a period of time, and involved EP-MRSI scans and clinical interviews on a monthly basis. Subjects with bipolar disorder had a diagnosis of bipolar I or II disorder and were between the ages of 18 and 65. They were either currently on a course of medication including lithium, depakote and other anticonvulsants, or were medication naïve at the start of the study. Subjects who were given anxiolytic medication during the scan sessions or who were taking medication in addition to those listed above were not considered in this study. Because of confounds in the medication changes for many of the subjects in these studies occurring after the initial visit, only mood improvement data from first visits was used.
The "Brief Affect Scale" (BAS) (Stoll, personal communication), which was administered to all subjects immediately before and after the MR scanning session, measures change in immediate mood state on a 7-point scale. These numerically ranked responses were grouped into the ordinal categories of "improved" (3 to 1), "same" (0) and "worse" (-1 to -3) for statistical treatment.
EP-MRSI Methods Studies were conducted at the McLean Hospital Brain Imaging Center. Scanning was performed on a General Electric 1.5T Signa MRI scanner (5.8 EchoSpeed version). At each clinic visit, 4 EP-MRSI scans were acquired, along with 30 minutes of anatomic MR scans. The EP-MRSI pulse sequence (PEPSI) has been extensively described (Posse et al 1997). The sham EP-MRSI exam was identical to original exam, except that the EP-MRSI scans were replaced with a 15 minute three-dimensioned spoiled gradient echo scan so that the duration of the sham EP-MRSI exam was the same. The electric and magnetic fields in EP-MRSI exams are presented in details in the Background and Significance section of this proposal.
Statistical Methods Ordered logistic regression modeling methods were used to examine the differences in BAS scores among the study groups. Data were summarized as means (±SD) or by means with 95% confidence intervals (95% CI). Two sided significance tests, requiring p<0.05 for statistical significance, were employed.
Results Twenty-three of 30 subjects with bipolar disorder reported improvement in mood of at least 1 point on the BAS scale after EP-MRSI exams. "No change" was reported by 7 subjects, and a worsening of mood was reported by 1 subject. The mean BAS score for bipolar EP-MRSI subjects scans was 0.87 ± 0.68. In the subgroup of medication naïve bipolar EP-MRSI subjects, 11 of 11 subjects reported improvement in mood (mean BAS score = 1.18 ± 0.41), compared to reports of improvement by 12 of 19 subjects with bipolar disorder in the subgroup taking mood stabilizing medication (mean BAS score 0.68 ± 0.75).
Three of 10 bipolar sham EP-MRSI subjects scans reported improvement in mood after the exam, with 2 reports of worsening in mood; the mean BAS score for bipolar sham EP-MRSI subjects scans was 0.30 ± 1.06. Four of 15 healthy subjects reported improvement in mood after an EP-MRSI exam, with no reports of worsening. The mean BAS score for healthy subjects who received EP-MRSI scans was 0.29 ± 0.47. Table 2 summarizes the BAS improvement scores.
Ordinal BAS ratings were compared between bipolar subjects who received actual EP-MRSI scans (N=30, mean BAS 0.87 ± 0.68) vs. those receiving sham EP-MRSI scans (N=10, mean BAS = 0.30 ± 1.06) using ordered logistic regression methods; this difference was statistically significant (z=2.63, p=0.009). The higher BAS scores in the actual EP-MRSI subjects indicate greater perceived mood improvement in this group compared to the bipolar sham EP-MRSI group.
Medication na±ve bipolar EP-MRSI subjects scans (N=11) had higher BAS scores (1.18 ± 0.41, Table 2) than bipolar EP-MRSI subjects scans that were receiving medication (N=19, mean BAS = 0.68 ± 0.75). This difference was statistically significant (z=2.02, p=0.044).
Ordinal BAS ratings were also compared between bipolar EP-MRSI subjects and healthy subjects who received EP-MRSI (N=14, mean BAS = 0.29 ± 0.47); this difference was also statistically significant (z=2.61, p=0.009). The contrast between bipolar sham EP-MRSI subjects and healthy EP-MRSI subjects was not significant (z=0.29, p=0.77). A summary of these results is listed in Table 3.
Table 1. Mood Improvement in Bipolar and Normal Subjects with EP-MRSI
|
|
N |
# improved |
# worse |
mean BAS |
|
Bipolar, EP-MRSI |
30 |
23 |
1 |
0.87 ± 0.68 |
|
- subgroup: medication naïve |
11 |
11 |
0 |
1.18 ± 0.41 |
|
- subgroup: on medication |
19 |
12 |
1 |
0.68 ± 0.75 |
|
Bipolar, sham EP-MRSI |
10 |
3 |
2 |
0.30 ± 1.06 |
|
Comparison, EP-MRSI |
14 |
4 |
0 |
0.29 ± 0.47 |
Table 2. Significance of Mood Improvement with EP-MRSI
|
|
Z |
p |
|
Bipolar, EP-MRSI vs. Bipolar, sham EP-MRSI |
2.63 |
0.009 |
|
subgroups: Bipolar, EP-MRSI, medication naïve vs. Bipolar, EP-MRSI, on medication |
2.02 |
0.044 |
|
Bipolar, EP-MRSI vs. Comparison, EP-MRSI |
2.61 |
0.009 |
|
Comparison, EP-MRSI vs. Bipolar, sham EP-MRSI |
0.29 |
0.77 |
Summary We have found significant improvement of mood in subjects with bipolar disorder after EP-MRSI scans. This change was absent in bipolar subjects that had sham EP-MRSI scans, and was also absent in healthy subjects that had the EP-MRSI scan. A greater effect was evident in medication naïve subjects with bipolar disorder.
This prospective pilot study has a number of limitations. A change in MRI system during the study with a corresponding suspension in EP-MRSI exams limited the size of the group receiving the sham EP-MRSI. Although data from several visits were available for some subjects, medication changes over time were confounded with changes associated with EP-MRSI scans, so that the analyses reported here had to be limited to first visit data. Also, the serendipitous use of existing study samples may be considered to be a limitation. The consistent and statistically significant rates of reported mood improvement, however, suggest that there is a significant neurobiological effect present.
The immediate improvement shown in the BAS scores indicates a surprising response to this treatment (77% responders), particularly in the medication naïve subjects (100% responders) vs. the subjects taking medication (63% responders) vs. the subjects receiving sham EP-MRSI (30% responders).
These preliminary data suggest that the EP-MRSI scan induces electric fields that are associated with reported mood improvement in bipolar subjects. Overall response rates are consistent with rates reported in current rTMS depression treatment trials, the rate of mood improvement was much higher for unmedicated subjects. The effect noted here suggests that antidepressant effects possibly could be elicited with more uniform, deeply penetrating magnetic and electric fields, using different timing parameters than previously used in rTMS
