A Pilot Investigation of Repetitive Transcranial Magnetic Stimulation for Post-Traumatic Brain Injury Depression: Safety, Tolerability, and Efficacy.

Depression following a traumatic brain injury (TBI) is common and difficult to treat using standard approaches. The current study investigated, for the first time, transcranial magnetic stimulation (TMS) for the treatment of post TBI depression. We specifically assessed the safety, tolerability, and efficacy of TMS in this patient population. We also explored cognitive outcomes. Twenty-one patients with a current episode of major depression subsequent to a TBI participated in a randomized double-blind placebo-controlled trial of repetitive TMS (rTMS). Sequential bilateral rTMS (to the left and right dorsolateral prefrontal cortex) was provided in 20 treatments over a period of 4 weeks. Patients were randomly allocated to receive either active or sham stimulation. There were no adverse effects and treatment was well tolerated. There was no significant effect of rTMS on post-TBI depression, with all patients showing a significant improvement in depressive symptoms irrespective of their treatment group (p = 0.002). There were significant improvements in cognition following active rTMS in the areas of working memory (p = 0.021) and executive function (p = 0.029). rTMS was shown to be safe and well tolerated in patients who had developed depression after a TBI. We did not find a therapeutic effect for post-TBI depression; however, this approach may have some utility in improving cognitive function. Future research should focus on alternative rTMS treatment approaches for post-TBI depression and the direct investigation of rTMS as a treatment for cognitive impairment in TBI.

Exploring alternative rTMS strategies in non-responders to standard high frequency left-sided treatment: A switching study.

BACKGROUND: High-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) is now commonly used treatment for patients with depression. However, there are several other forms of rTMS (low-frequency right-sided and sequential bilateral rTMS) which have also been shown to be effective. No information has been systematically gathered on the likelihood of response to alternative forms of rTMS in patients who do not improve after an initial course of left-sided treatment. OBJECTIVE: To evaluate whether there are differences in antidepressant response between switching to either low-frequency right sided or sequential bilateral stimulation or continuing high-frequency left-sided TMS following non-response to an initial course of high-frequency left-sided rTMS. METHODS: 113 rTMS naïve patients were provided with an initial three-week course of high-frequency left-sided rTMS. Non-responders were then randomised to receive another three weeks of left-sided treatment (n = 21), right-sided low frequency stimulation (n = 18) or sequential bilateral rTMS (n = 20). RESULTS: Although there was an overall improvement in depressive symptoms in the randomised phase of the study, no significant differences in response was seen between the three treatment groups on Montgomery Asberg Depression Rating Scale or Hamilton Depression Rating Scale scores. LIMITATIONS: The main limitation of the study was the duration of treatment provided in both the lead in and random treatment phases. CONCLUSION: This study does not provide evidence for differences in response to different forms of rTMS in initial non-responders to left-sided stimulation. However, further studies with longer periods of treatment and a larger sample size are required to definitively establish or exclude between group differences in rTMS response in initial non-responders to treatment.

A pilot study of the comparative efficacy of 100 Hz magnetic seizure therapy and electroconvulsive therapy in persistent depression.

BACKGROUND: Magnetic seizure therapy (MST) is a novel brain stimulation technique that uses a high-powered transcranial magnetic stimulation device to produce therapeutic seizures. Preliminary MST studies have found antidepressant effects in the absence of cognitive side effects but its efficacy compared to electroconvulsive therapy (ECT) remains unclear. The aim of this study was to investigate the therapeutic efficacy and cognitive profile of MST compared to standard right unilateral ECT treatment. METHODS: Thirty-seven patients completed a course of at least nine ECT or MST treatments in a randomized double-blind protocol. Assessments of depression severity and cognition were performed before and after treatment. RESULTS: No difference in the antidepressant effectiveness between the treatments was seen across any of the clinical outcome measures, although the overall response rates in both groups were quite low. In regards to cognition, following MST there were significant improvements in tests of psychomotor speed, verbal memory, and cognitive inhibition, with no reductions in cognitive performance. Following ECT there was significant improvement in only one of the cognitive inhibition tasks. With respect to the between-group comparisons, the MST group showed a significantly greater improvement on psychomotor speed than ECT. CONCLUSIONS: MST showed similar efficacy to right unilateral ECT in patients with treatment-resistant depression without cognitive side effects but in a sample that was only of sufficient size to demonstrate relatively large differences in response between the two groups. Future research should aim to optimize the methods of MST administration and compare its efficacy to ECT in large randomized controlled trials.

Modular organization of the multipartite central pattern generator for turtle rostral scratch: knee-related interneurons during deletions.

Central pattern generators (CPGs) are neuronal networks in the spinal cord that generate rhythmic patterns of motor activity in the absence of movement-related sensory feedback. For many vertebrate rhythmic behaviors, CPGs generate normal patterns of motor neuron activities as well as variations of the normal patterns, termed deletions, in which bursts in one or more motor nerves are absent from one or more cycles of the rhythm. Prior work with hip-extensor deletions during turtle rostral scratch supports hypotheses of hip-extensor interneurons in a hip-extensor module and of hip-flexor interneurons in a hip-flexor module. We present here single-unit interneuronal recording data that support hypotheses of knee-extensor interneurons in a knee-extensor module and of knee-flexor interneurons in a knee-flexor module. Members of knee-related modules are not members of hip-related modules and vice versa. These results in turtle provide experimental support at the single-unit interneuronal level for the organizational concept that the rostral-scratch CPG for the turtle hindlimb is multipartite, that is, composed of more than two modules. This work, when combined with experimental and computational work in other vertebrates, does not support the classical view that the vertebrate limb CPG is bipartite with only two modules, one controlling all the flexors of the limb and the other controlling all the extensors of the limb. Instead, these results support the general principle that spinal CPGs are multipartite.

A negative double-blind controlled trial of sequential bilateral rTMS in the treatment of bipolar depression.

BACKGROUND/OBJECTIVE: To explore the therapeutic benefit of sequential bilateral repetitive transcranial magnetic stimulation (rTMS) in the treatment of bipolar depression. METHOD: A 2 arm randomized controlled parallel design trial comparing the use of active sequential bilateral rTMS to a sham form of stimulation in 49 patients with bipolar disorder and treatment resistant depression. RESULTS: There was no significant difference in mean reduction in depression rating scale scores or response rates between active and sham stimulation. LIMITATIONS: The study was of limited sample size and the use of bilateral rTMS limited generalizability to other forms of rTMS. CONCLUSIONS: This study provides no support to the use of active sequential bilateral rTMS in the treatment of the depressive phase of bipolar affective disorder. Although this result is not definitive, we suggest that future research may be better focused on trials evaluating the use of unilateral types of rTMS.

Factors to consider when applying transcranial magnetic stimulation of dorsolateral prefrontal cortex when resting motor threshold is asymmetric: A case study.

Transcranial magnetic stimulation (TMS) is an increasingly popular tool in treating psychiatric conditions. The dorsal lateral prefrontal cortex (DLPFC) is typically targeted for stimulation, with magnetic field intensity being calibrated by establishing resting motor threshold (RMT) at hand region of primary motor cortex (M1 hand). This presumes that scalp-to-cortex distance (SCD) and cortical thickness is similar at both sites. We present data from a patient who had very asymmetrical RMTs (47 and 78). We investigated SCDs in this patient at the M1 hand and DLPFC, and the M1 hand cortical thickness. We also investigated TMS electric field distribution. The M1 hand SCD and cortical thickness of the M1 hand was larger on the side with higher RMT. Electric field finite element modelling demonstrated the focal point did not effectively reach the M1 hand with higher RMT as the postcentral gyrus was shunting it. Hence, successful DLPFC treatment was based upon the side with lower RMT. This study highlights the importance of tailoring DLPFC treatment intensity not only based on RMT at the M1 hand, and upon the degree to which SCD distance differs between sites, but also based upon size, shape, and density of M1 hand, as well as electric field distribution.

A negative pilot study of daily bimodal transcranial direct current stimulation in schizophrenia.

BACKGROUND: A small number of studies conducted to date have suggested that transcranial direct current stimulation (tDCS) applied to the temporoparietal cortex may reduce auditory hallucinations in patients with schizophrenia. Prefrontal brain stimulation with other methods, has also been shown to potentially improve the negative symptoms of this disorder. OBJECTIVE: To investigate the therapeutic potential of daily bimodal tDCS: anodal stimulation to the prefrontal cortex and cathodal stimulation to the temporoparietal junction in patients with persistent hallucinations and negative symptoms of schizophrenia. METHODS: We conducted two small randomized double-blind controlled trials comparing bimodal tDCS to sham stimulation. In one study, stimulation was provided unilaterally, in the second study it was provided bilaterally. RESULTS: Neither unilateral nor bilateral tDCS resulted in a substantial change in either hallucinations or negative symptoms. Stimulation was well tolerated without side-effects. CONCLUSION: Daily tDCS does not appear to have substantial potential in the treatment of hallucinations or negative symptoms and further research should investigate higher doses of stimulation or more frequently applied treatment schedules.

Volumetric, cortical thickness and white matter integrity alterations in bipolar disorder type I and II.

BACKGROUND: Bipolar disorder (BD) is a debilitating psychiatric disorder affecting millions of people worldwide with mean time to diagnosis estimated to be at least 10 years. Whilst many brain imaging studies have compared those with BD to controls, few have attempted to investigate differences between BD Type I and II and matched controls. METHODS: Thirty-one patients with BD (16 Type I and 15 Type II) and 31 matched healthy controls were MRI brain scanned with conventional T1-weighted and diffusion tensor imaging methods. RESULTS: There was significantly reduced regional brain volume and thickness among the BD subjects, but also between BD Type I when compared to Type II. White matter integrity also differed between the groups and BD severity correlated significantly with regional brain volume and thickness. LIMITATIONS: Future investigations will consider length of time each BD patient had been diagnosed with BD, as well as assessing controls for family history of psychiatric illness, specifically BD. Similarly, genetic assessment will be conducted as well. CONCLUSIONS: These findings suggest that there are not only regional brain volumetric, thickness and white matter integrity differences between BD and matched controls, but also between those with BD Type I and Type II, such that reduced regional brain volume may underlie BD Type I whereas white matter integrity is more altered in BD Type II.

A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression.

OBJECTIVE: A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS. METHOD: Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD). RESULTS: In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups. CONCLUSIONS: This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS.

Transcranial magnetic stimulation for depression after a traumatic brain injury: a case study.

Depression after a traumatic brain injury (TBI) is very common, yet there is a lack of evidence-based treatment options for people who experience depression after a TBI. Traditionally, a history of TBI has been considered an exclusion criterion for transcranial magnetic stimulation trials because of the increased risk of seizure after a TBI. We present what we believe to be the first case of a patient with depression after a TBI treated with transcranial magnetic stimulation.

A study of the effectiveness of high-frequency left prefrontal cortex transcranial magnetic stimulation in major depression in patients who have not responded to right-sided stimulation.

The objective of this study was to explore the response rate to high-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) in patients who had failed to respond to right-sided low-frequency stimulation, and to investigate whether there was differential efficacy between stimulation at 5 or 10 Hz. Data from two randomized controlled trials were pooled. In both studies a group of patients were randomized to receive either 5- or 10-Hz left prefrontal rTMS after failing to respond to right-sided stimulation. These patients received blinded 5- or 10-Hz stimulation (but without a sham control) for a period of up to 4 weeks and outcomes were compared. There was a small but significant overall response to left-sided rTMS but no difference in response between the 5- and 10-Hz treatment conditions. There appears to be a significant but modest likelihood of response to left-sided TMS in patients who fail right-sided stimulation, but there is no difference in efficacy between 5- and 10-Hz stimulation.

A randomized trial of rTMS targeted with MRI based neuro-navigation in treatment-resistant depression.

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject's MRI scan. There was an overall significant reduction in the Montgomery-Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.

Priming stimulation enhances the effectiveness of low-frequency right prefrontal cortex transcranial magnetic stimulation in major depression.

OBJECTIVES: Low-frequency, right-sided repetitive transcranial magnetic stimulation (rTMS) to the prefrontal cortex has been shown to have antidepressant effects. Recent research has suggested that preceding low-frequency rTMS with a period of low-intensity, 6-Hz stimulation ("priming") enhances the physiological effects of low-frequency stimulation. The aim of this study was to investigate whether priming stimulation would enhance therapeutic response to low-frequency rTMS in patients with depression. METHOD: The study consisted of a 2-arm, double-blind, randomized, controlled trial in 60 patients with treatment-resistant depression. Right 1-Hz rTMS was provided in one continuous, 15-minute train to all subjects. The priming stimulation (twenty 5-second, 6-Hz trains) or an equivalent, sham preceded 1-Hz stimulation. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: There was a significant overall reduction in MADRS scores across the 4 weeks of the study and a significantly greater reduction in MADRS scores in the active-priming group compared with the sham-priming group. CONCLUSIONS: Low-intensity, high-frequency priming stimulation appears to enhance the response to low-frequency, right-sided rTMS treatment in patients with treatment-resistant depression.

A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is increasingly being investigated as a potential treatment for a number of psychiatric disorders, including schizophrenia. Previous rTMS studies have targeted the left-side prefrontal cortex (PFC) in the treatment of negative symptoms, with inconsistent findings. Some imaging evidence suggests right-sided or bilateral PFC involvement in negative symptoms, areas yet to be investigated for rTMS treatment. The study therefore aimed to assess the efficacy of bilateral high-frequency rTMS in the treatment of negative symptoms. METHODS: A 2-arm double-blind randomized controlled trial was conducted with 20 patients with a diagnosis of schizophrenia or schizoaffective disorder, and moderate-to-severe treatment-resistant negative symptoms. Participants received a 3-week course of high-frequency bilateral rTMS or sham. Twenty trains (5 seconds duration) of 10 Hz rTMS at 110% of the RMT were administered to each PFC daily, 5 days a week. RESULTS: No significant group or time differences in the Scale for the Assessment of Negative Symptoms (SANS) scores or cognitive outcomes were evident. However, a trend for greater reduction in scores on the autistic preoccupation scale of the Positive and Negative Symptom Scale for the active group compared to the sham group was observed (P = .05). CONCLUSIONS: No substantial benefit of high-frequency bilateral rTMS was seen in the treatment of the negative symptoms of schizophrenia. Further research is required to explore whether rTMS may have benefits specific to particular cognitive or symptom domains.

Variations in motor patterns during fictive rostral scratching in the turtle: knee-related deletions.

Agonist motor neurons usually alternate between activity and quiescence during normal rhythmic behavior; antagonist motor neurons are usually active during agonist motor neuron quiescence. During an antagonist deletion, a naturally occurring motor-pattern variation, there is no antagonist activity and no quiescence between successive bursts of agonist activity. Motor neuron recordings of normal fictive rostral scratching in the turtle displayed rhythmic alternation between activity and quiescence for hip flexors, knee flexors, and knee extensors. Knee-flexor activity occurred during knee-extensor quiescence. During a hip-extensor deletion, a variation of rostral scratching, rhythmic hip-flexor bursts occurred without intervening hip-flexor quiescence. There were 3 distinct patterns of knee motor activity during the cycle before or after a hip-extensor deletion. In most cycles, there was knee flexor-extensor rhythmic alternation. In some cycles, termed knee-flexor deletions, there was no knee-flexor activity and rhythmic knee-extensor bursts occurred without intervening knee-extensor quiescence. In other cycles, termed knee-extensor deletions, there was no knee-extensor activity and rhythmic knee-flexor bursts occurred without intervening knee-flexor quiescence. The concept of a module refers to a population of motor neurons and interneurons with similar activity patterns; interneurons in a module coordinate agonist and antagonist motor neuron activities, either with excitation of agonist motor neurons and interneurons, or with inhibition of antagonist motor neurons and interneurons. Previous studies of hip-extensor deletions support the concept of a rhythmogenic hip-flexor module. The knee-related deletions described here support the concept of rhythmogenic knee-flexor and knee-extensor modules linked by reciprocal inhibition.

Timing of knee-related spinal neurons during fictive rostral scratching in the turtle.

Knee-flexor motor activity rhythmically alternated with knee-extensor motor activity during fictive rostral scratching in the spinal turtle. A critical transition from knee-flexor motor activity to knee-extensor motor activity occurred during hip-flexor motor activity. A key feature of this transition was that the end-phases of knee-flexor motor activity were positively correlated with the start-phases of knee-extensor motor activity. We studied spinal interneurons with activities related to this transition. We previously used single-unit recording techniques to characterize a data set of descending propriospinal interneurons during rostral scratching. We focused here on a group of interneurons from this data set with start-phases (on-units) or with end-phases (off-units) near the start of knee-extensor motor activity. We showed that, for a subset of these units, the start-phases of on-units and the end-phases of off-units were positively correlated with the start-phases of knee-extensor motor activity. We present the hypothesis that some of these knee-related on- and off-units may play a role in timing knee motor activity during rostral scratching.

Modular organization of turtle spinal interneurons during normal and deletion fictive rostral scratching.

During normal rostral scratching in the spinal turtle, there is rhythmic alternation between hip-flexor and hip-extensor motor activity. During rostral scratching with hip-extensor deletions, there are successive bursts of hip-flexor motor activity and no activity in hip-extensor motor neurons. We characterized the ON- and OFF-phases of 72 descending propriospinal interneurons with distinct activity bursts during normal rostral scratching. We also studied the activity of these interneurons during deletion scratching. Hip-extensor interneurons were active when hip-flexor motor neurons were quiet in normal scratching and had zero overlap with hip-flexor motor activity. This population of hip-extensor interneurons, termed the hip-extensor module or hip-extensor unit-burst generator, was mainly quiet during deletion scratching. Our observation supports the concept that a module is a neuronal population that may be active or quiet in a coordinated manner during a spinal motor rhythm. During normal scratching, hip-flexor interneurons were active during hip-flexor motor activity, and spanning interneurons were active during both hip-flexor motor activity and quiescence. Hip-flexor and spanning interneurons with intermediate overlap with hip-flexor motor activity fired in bursts during deletion scratching. Hip-flexor and spanning interneurons with large overlap with hip-flexor motor activity fired continuously during deletion scratching. Key features of hip-flexor and spanning interneuron firing during normal scratching were preserved during deletion scratching. Thus these features do not require activity in the hip-extensor module in every cycle of a motor rhythm.