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Deregulation of the Anterior Cingulate Cortex as a Mediator of TMS Outcomes in Complex MDD
Laura Viner, Jesse Viner, Leah Klein, and Emily Rose Kirschenbaum
Psychiatry and Behavioral Sciences, Northwestern University Medical School, and Yellowbrick
Transcranial Magnetic Stimulation
(TMS) is well established as a
beneficial alternative or supplement
to medication for treatment-
resistant Major Depressive Disorder
(MDD). Despite its success with
many patients, there are still
individuals who do not respond
sufficiently or who have such
complex and multi-dimensional
Axis I and Axis II Disorders that
they are not good TMS candidates.
In treatment-resistant depression,
Mayberg and colleagues (1997; 2005)
demonstrated that deregulated
brain regions involved in emotional
processing and responding mediate
outcomes for pharmacotherapy and
other neurobiological treatments
such as deep brain stimulation.
They identified the prefrontal and,
especially, the cingulate cortex as
central to emotional and cognitive
processing in depression because of
their critical connections between
the limbic system and the cortex.
Based on previous findings by
Mayberg and others, this study
examined potential mediators of
TMS response among extremely
complex and severely treatment-
resistant patients, namely,
deregulation of the anterior
cingulate, prefrontal, and/or frontal
cortex.
The results showed that improvement
Pre- to Post-TMS on the MADRS
(t=4.43, p=.0002) and the BDI (t=2.38,
p=.02) were significantly poorer for
patients whose anterior cingulate
cortices were at least 2 standard
deviations more deregulated than a
large-scale normative database (see
Figures 1, 2 and 3 below). TMS
outcomes for prefrontal cortex
deregulation showed a trend and
frontal deregulation was not
significant.
These findings suggest that TMS
outcomes in complex MDD may be
mediated by deregulation of the anterior
cingulate cortex. Individuals with
complex and severe MDD, who had
deregulated anterior cingulate cortices,
did not improve with TMS treatment.
However, despite their complexity and
severity, those who had regulated
anterior cingulate cortices did improve
on average by 41% on the BDI and 38%
on the MADRS. These improvements
are comparable to those reported for the
“typical” treatment-resistant MDD
patients who meet criteria for TMS
outcome studies: whereas none of the
individuals in the present sample would
meet criteria for TMS treatment in any of
the multi-center outcome studies of
either Brainsway or Neurostar. These
findings are consistent with Mayberg’s
findings for deep brain stimulation
(DBS) and offer hope for many
individuals who have severe and
complex depression and who may
improve significantly with TMS. The
findings here also suggest that it may be
more beneficial to target the anterior
cingulate cortex, perhaps in addition to
the primary prefrontal target, in TMS
treatments for those patients who are
deregulated in this area at baseline.
Introduction Results Discussion
Response to TMS treatment was
compared among 26 severe and
complex MDD patients with either a
regulated or deregulated anterior
cingulate, prefrontal, and/or frontal
cortex, upon pre-treatment
assessment. There were 14 male and
12 female participants, and their
average age was 23.5 years old. The
participants had an average of 5 Axis-
1 SCID diagnoses, as assessed by 2
senior psychiatrists. Of the total
participants, 58% had a history of at
least one serious suicide attempt and
40% had made multiple suicide
attempts that required acute
hospitalization (in most cases). To
assess real-time neurophysiological
deregulation of localized brain
regions, we used the quantitative
electroencephalogram (qEEG), with a
standard 10/20 EEG array during Eyes
Closed. We also employed
Neuroguide software for LORETA 3-
dimensional source analysis.
Brainsway or Neurostar TMS
standard treatment protocols were
applied for successive patients at
Yellowbrick, an intensive, residential
neurobiological treatment facility near
Chicago, Illinois. Both the Brainsway
and the Neurostar TMS machines
direct the electromagnetic pulses at
the prefrontal cortex; however the
Brainsway deep TMS machine reaches
250% deeper than does the Neurostar.
The measures of treatment response
included the Montgomery-Asberg
Depression Rating Scale (MADRS)
and the Beck Depression Inventory
(BDI).
Method
Levkovitz, Y., Isserles, M. et al. (2015). Efficacy and safety of deep
transcranial magnetic stimulation for major depression: A prospective
multicenter randomized controlled trial. World Psychiatry,14, 64-73.
Mayberg, H.S., Brannan, S.K. et al (1997). Cingulate function in
depression: A potential predictor of treatment response. Neuroreport, 8,
1057-61.
Mayberg, H. S., Lozano, A.M. et al. (2005). Deep brain stimulation for
treatment-resistant depression. Neuron, 45, 651-60.
O’Reardon, J.P., Solvason, H.B. et al. (2007). Efficacy and safety of
transcrnial magnetic sti,mulation in the acute treatment of major
depression: A multicenter randomized controlled trial. Biol. Psychiat.,
62, 1208-16,
References
https://www.yellowbrickprogram.com
Figure 1. MADRS scores comparing pre and post TMS scores among
regulated and deregulated anterior cortex patients.
Figure 2. BDI scores comparing pre and post TMS scores among
regulated and deregulated anterior cortex patients.
Figure 3. Example of Loretta Analysis of the Anterior Cingulate Cortex in a
deregulated Pre-TMS Patient.

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TMS poster -10-8-15 (3)

  • 1. Deregulation of the Anterior Cingulate Cortex as a Mediator of TMS Outcomes in Complex MDD Laura Viner, Jesse Viner, Leah Klein, and Emily Rose Kirschenbaum Psychiatry and Behavioral Sciences, Northwestern University Medical School, and Yellowbrick Transcranial Magnetic Stimulation (TMS) is well established as a beneficial alternative or supplement to medication for treatment- resistant Major Depressive Disorder (MDD). Despite its success with many patients, there are still individuals who do not respond sufficiently or who have such complex and multi-dimensional Axis I and Axis II Disorders that they are not good TMS candidates. In treatment-resistant depression, Mayberg and colleagues (1997; 2005) demonstrated that deregulated brain regions involved in emotional processing and responding mediate outcomes for pharmacotherapy and other neurobiological treatments such as deep brain stimulation. They identified the prefrontal and, especially, the cingulate cortex as central to emotional and cognitive processing in depression because of their critical connections between the limbic system and the cortex. Based on previous findings by Mayberg and others, this study examined potential mediators of TMS response among extremely complex and severely treatment- resistant patients, namely, deregulation of the anterior cingulate, prefrontal, and/or frontal cortex. The results showed that improvement Pre- to Post-TMS on the MADRS (t=4.43, p=.0002) and the BDI (t=2.38, p=.02) were significantly poorer for patients whose anterior cingulate cortices were at least 2 standard deviations more deregulated than a large-scale normative database (see Figures 1, 2 and 3 below). TMS outcomes for prefrontal cortex deregulation showed a trend and frontal deregulation was not significant. These findings suggest that TMS outcomes in complex MDD may be mediated by deregulation of the anterior cingulate cortex. Individuals with complex and severe MDD, who had deregulated anterior cingulate cortices, did not improve with TMS treatment. However, despite their complexity and severity, those who had regulated anterior cingulate cortices did improve on average by 41% on the BDI and 38% on the MADRS. These improvements are comparable to those reported for the “typical” treatment-resistant MDD patients who meet criteria for TMS outcome studies: whereas none of the individuals in the present sample would meet criteria for TMS treatment in any of the multi-center outcome studies of either Brainsway or Neurostar. These findings are consistent with Mayberg’s findings for deep brain stimulation (DBS) and offer hope for many individuals who have severe and complex depression and who may improve significantly with TMS. The findings here also suggest that it may be more beneficial to target the anterior cingulate cortex, perhaps in addition to the primary prefrontal target, in TMS treatments for those patients who are deregulated in this area at baseline. Introduction Results Discussion Response to TMS treatment was compared among 26 severe and complex MDD patients with either a regulated or deregulated anterior cingulate, prefrontal, and/or frontal cortex, upon pre-treatment assessment. There were 14 male and 12 female participants, and their average age was 23.5 years old. The participants had an average of 5 Axis- 1 SCID diagnoses, as assessed by 2 senior psychiatrists. Of the total participants, 58% had a history of at least one serious suicide attempt and 40% had made multiple suicide attempts that required acute hospitalization (in most cases). To assess real-time neurophysiological deregulation of localized brain regions, we used the quantitative electroencephalogram (qEEG), with a standard 10/20 EEG array during Eyes Closed. We also employed Neuroguide software for LORETA 3- dimensional source analysis. Brainsway or Neurostar TMS standard treatment protocols were applied for successive patients at Yellowbrick, an intensive, residential neurobiological treatment facility near Chicago, Illinois. Both the Brainsway and the Neurostar TMS machines direct the electromagnetic pulses at the prefrontal cortex; however the Brainsway deep TMS machine reaches 250% deeper than does the Neurostar. The measures of treatment response included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI). Method Levkovitz, Y., Isserles, M. et al. (2015). Efficacy and safety of deep transcranial magnetic stimulation for major depression: A prospective multicenter randomized controlled trial. World Psychiatry,14, 64-73. Mayberg, H.S., Brannan, S.K. et al (1997). Cingulate function in depression: A potential predictor of treatment response. Neuroreport, 8, 1057-61. Mayberg, H. S., Lozano, A.M. et al. (2005). Deep brain stimulation for treatment-resistant depression. Neuron, 45, 651-60. O’Reardon, J.P., Solvason, H.B. et al. (2007). Efficacy and safety of transcrnial magnetic sti,mulation in the acute treatment of major depression: A multicenter randomized controlled trial. Biol. Psychiat., 62, 1208-16, References https://www.yellowbrickprogram.com Figure 1. MADRS scores comparing pre and post TMS scores among regulated and deregulated anterior cortex patients. Figure 2. BDI scores comparing pre and post TMS scores among regulated and deregulated anterior cortex patients. Figure 3. Example of Loretta Analysis of the Anterior Cingulate Cortex in a deregulated Pre-TMS Patient.